Compounds and methods

ABSTRACT

Disclosed are compounds having the formula: 
     
       
         
         
             
             
         
       
     
     wherein X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , Y, A, Z, L and n are as defined herein, and methods of making and using the same.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds that inhibit histonedeacetylase (HDAC) enzymes, the preparation of these compounds, the useof these compounds in the treatment of diseases or conditionsameliorated by inhibition of HDAC activity and pharmaceuticalcompositions comprising these compounds.

2. Background of the Invention

Chromatin organization involves DNA wound around histone octamers thatform nucleosomes. Core histones with N-terminal tails extending fromcompact nucleosomal core particles can be acetylated or deacetylated atepsilon lysine residues affecting histone—DNA and histone—non-histoneprotein interactions. Histone deacetylases (HDACs) catalyze thedeacetylation of histone and non-histone proteins and play an importantrole in epigenetic regulation. There are currently 18 known HDACs thatare organized into three classes: class I HDACs (HDAC1, HDAC2, HDAC3,HDAC8 and HDAC11) are mainly localized to the nucleus; class II HDACs(HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10), which shuttle betweenthe nucleus and the cytoplasm; and class III HDACs (SIRT1-7), whosecellular localization includes various organelles.

Class II HDACs are further characterized as class IIa HDACs and classIIb HDACs.

HDAC9 is class IIa histone deacetylase highly expressed in human Tregs.HDAC9 deficiency: 1) increases Foxp3 expression (and other Tregmarkers), 2) increases Foxp3 and histone 3 acetylation, 3) increasesFoxp3 DNA binding, 4) increases Treg numbers, 5) increases suppressiveactivity in vitro and in vivo, and 6) ameliorates murine colitis. Tregswhich are deficient in HDAC9 induce permanent tolerance of fullymismatched cardiac allografts. In addition, HDAC9 inhibitors maybeuseful for treatment of diseases and disorders associated with abnormalcell proliferation, differentiation and survival, e.g. breast andprostate tumors.

Preliminary data shows that targeting HDAC7, a class IIa histonedeacetylase, enhances Treg suppression in vitro and in vivo. HDAC7enhances FOXP3+ Treg function and induces long-term allograft survival.

Inhibition of HDAC6, a class IIb HDAC, has been shown to increase Tregsuppressive function in vitro along with increased expression of FOXP3protein and Treg associated genes including CTLA, IL-10, TNR18. HDAC6inhibition in vivo decreased severity of colitis in the dextran sodiumsulphate-induced colitis model and the CD4+CD62Lhigh adoptive transfermodel of colitis. In addition, inhibition of HDAC6 with a subtherapeuticdose of rapamycin led to prolonged cardiac allograft survival.

Based on the above evidence, an orally available small moleculeselective inhibitor of Class II HDAC activity (more specifically HDAC9or HDAC7 or HDAC6) is expected to modulate autoimmune diseases throughexpansion and enhancement of Treg activity.

Inhibition of other Class II HDAC's for example HDAC4 and 5 impairmyogenesis by modulating the stability and activity of HDAC-MEF2complexes and maybe potentially useful for the treatment of muscle andheart diseases including cardiac hypertrophy and heart failure. Also,inhibition of Class II HDAC activity, represents a novel approach fordisrupting or intervening in cell cycle regulation.

Class II HDAC inhibitors have therapeutic potential in the study and/ortreatment of diseases or conditions ameliorated by modulating HDACactivity (in particular, cell proliferative diseases (such as cancer),diabetes (type I and/or type II diabetes), inflammation, cardiacdisease, obesity, stroke, epilepsy, depression, immunological disease orviral or fungal infection.

Many HDAC inhibitors, however, inhibit all HDAC isoforms. It would beadvantageous to identify HDAC inhibitors that inhibited one or more butnot all HDAC isoforms.

SUMMARY OF THE INVENTION

The invention is directed to a compound according to Formula I:

wherein:

R¹ is halo(C₁-C₄)alkyl, wherein said halo(C₁-C₄)alkyl contains at least2 halo groups;

Y is a bond and X₁ is O, N or NH, X₂ is N or CH and X₃ is N or NH,

or Y is —C(O)— and X₁ and X₂ are CH or N, X₃ is O or S,

or Y is —C(O)— and X₁ is O, X₂ is CH or N, and X₃ is CH or N;

A is optionally substituted (C₃-C₆)cycloalkyl, phenyl, naphthyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 memberedheteroaryl,

wherein any optionally substituted cycloalkyl, phenyl, naphthyl,heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A);

Z is —C(═O)NR^(X)—, —NR^(X)C(═O)NR^(X), —NR^(X)C(═O)—, —SO₂—,—SO₂NR^(X)—, —NR^(X)SO₂—, —NHCH(CF₃)—, —CH(CF₃)NH—, —CH(CF₃)—,—(C₁-C₄)alkyl-, —NR^(X)—, or —(C₁-C₃)alkyl-NR^(X)—;

n is 0-4;

when n is 0, R² and R³ are independently selected from H and optionallysubstituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-,

when n is 1-4, R² and R³ are independently selected from H, fluoro, andoptionally substituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, wherein, when n is 1, R² is F and R³ isH, then Z is —C(═O)NR^(X)—, —NR^(X)C(═O)NR^(X), —SO₂NR^(X)—,—NHCH(CF₃)—, —CH(CF₃)NH—, —CH(CF₃)—, —(C₁-C₄)alkyl-, —NR^(X)—, or—(C₁-C₃)alkyl-NR^(X)—, and

when n is 1-4, R² is selected from —NR^(A)R^(B),—(C₁-C₄)alkyl-NR^(A)R^(B), —CONR^(A)R^(B), —(C₁-C₄)alkyl-CONR^(A)R^(B),—CO₂H, —(C₁-C₄)alkyl-CO₂H, hydroxyl, hydroxy(C₁-C₄)alkyl-,(C₁-C₃)alkoxy, and (C₁-C₃)alkoxy(C₁-C₄)alkyl-, and R³ is selected from Hand optionally substituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-,

wherein the aryl, cycloalkyl and each of the (C₁-C₄)alkyl moieties ofsaid optionally substituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl- of any R² and R³ are optionallysubstituted by 1, 2 or 3 groups independently selected from halogen,cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,—NR^(A)R^(A), —((C₁-C₄)alkyl)NR^(A)R^(A), and hydroxyl;

or R² and R³ taken together with the atom to which they are connectedform an optionally substituted 4, 5, 6, or 7 membered cycloalkyl orheterocycloalkyl group, wherein said heterocycloalkyl group contains 1or 2 heteroatoms independently selected from N, O and S and saidoptionally substituted cycloalkyl or heterocycloalkyl group isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, halogen, cyano, aryl(C₁-C₄)alkyl-,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, —OR^(Y), —NR^(Y)R^(Y), —C(═O)OR^(Y),—C(═O)NR^(Y)R^(Y), —NR^(Y)C(═O)R^(Y), —SO₂NR^(Y)R^(Y), —NR^(Y)SO₂R^(Y),—OC(═O)NR^(Y)R^(Y), —NR^(Y)C(═O)OR^(Y), and —NR^(Y)C(═O)NR^(Y)R^(Y); and

L is 5-6 membered heteroaryl or phenyl which is substituted by R⁴ and isoptionally further substituted,

wherein when L is further substituted, L is substituted by 1 or 2substituents independently selected from halogen, cyano and(C₁-C₄)alkyl;

R⁴ is H, (C₁-C₄)alkyl, halo, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkoxy,((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkyl-, (C₁-C₄)haloalkoxy-,(C₁-C₄)alkylamino, optionally substituted (C₃-C₆)cycloalkyl, optionallysubstituted phenyl, optionally substituted 5-6 memberedheterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,

wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkylor heteroaryl is optionally substituted by 1, 2 or 3 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio-, halo(C₁-C₄)alkoxy,hydroxyl, —NR^(A)R^(C) and —((C₁-C₄)alkyl)NR^(A)R^(C);

or L-R⁴, taken together, form a 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl orisoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl orisoindolinyl group is optionally substituted by 1, 2 or 3 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio-, halo(C₁-C₄)alkoxy,hydroxyl, —NR^(A)R^(C) and —((C₁-C₄)alkyl)NR^(A)R^(C);

wherein each R^(A) is independently selected from H and (C₁-C₄)alkyl;

R^(B) is H, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, —C(═O)(C₁-C₄)alkyl,—C(═O)O(C₁-C₄)alkyl, —C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl,—C(═O)N((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl, or R^(A) andR^(B) taken together with the atom to which they are attached form a 4-6membered heterocyclic ring, optionally containing one additionalheteroatom selected from N, O and S and optionally substituted by(C₁-C₄)alkyl;

R^(C) is H, (C₁-C₄)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6membered heteroaryl, or R^(A) and R^(C) taken together with the atom towhich they are attached form a 4-8 membered heterocyclic ring,optionally containing one additional heteroatom selected from N, O and Sand optionally substituted by (C₁-C₄)alkyl;

each R^(X) is independently selected from H, (C₁-C₆)alkyl, andoptionally substituted (C₂-C₆)alkyl, where said optionally substituted(C₂-C₆)alkyl is optionally substituted by hydroxyl, cyano, amino,(C₁-C₄)alkoxy, (C₁-C₄)alkyl)NH—, or ((C₁-C₄)alkyl)((C₁-C₄)alkyl)N—; and

each R^(Y) is independently selected from H, (C₁-C₄)alkyl, phenyl, and—(C₁-C₄)alkylphenyl;

or a salt thereof, or a salt, particularly a pharmaceutically acceptablesalt, thereof, and is further directed to a pharmaceutical compositioncomprising the compound of Formula I, or a salt thereof, a method ofinhibiting HDAC by contacting a HDAC with the compound of Formula I or asalt thereof, and a method of treating a subject having a disease ordisorder mediated by inhibition of a HDAC comprising administering thecompound of Formula I, or a salt thereof, or a pharmaceuticalcomposition comprising the compound of Formula I, or a salt thereof, tothe subject.

In one embodiment, a compound of Formula I excludes the followingcompounds:

-   N-[(4-fluorophenyl)methyl]-4-[5-(2,2,2-trifluoroacetyl)-2-thienyl]-benzamide-   N-[(4-fluorophenyl)methyl]-3-[5-(2,2,2-trifluoroacetyl)-2-thienyl]-benzamide,-   4-methoxy-N-[2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]-3-thienyl]-benzeneacetamide,-   N-[(4-methoxyphenyl)methyl]-4-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine,-   4-(trifluoromethyl)-N-[3-(trifluoromethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]-benzenepropanamide,-   3-[4-(trifluoromethyl)phenyl]-N-{3-(trifluoromethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl}propanamide,-   3-{7-methyl-2-[4-(3-methyl-5-isoxazolyl)butyl]-1-benzofuran-5-yl}-5-(trifluoromethyl)-1,2,4-oxadiazole,-   1-[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,    7-methyl-1-[4-(3-methyl-5-isoxazolyl)butyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,-   7-methyl-1-[5-(3-methyl-5-isoxazolyl)pentyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,-   7-methyl-1-[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indole,    or-   N-(phenylmethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine;

or a salt thereof.

The invention is further directed to a pharmaceutical compositioncomprising a compound of the invention. The invention is still furtherdirected to methods of inhibiting HDAC enzymes and treatment ofconditions associated therewith using a compound of the invention or apharmaceutical composition comprising a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The alternative definitions for the various groups and substituentgroups of Formula I provided throughout the specification are intendedto particularly describe each compound species disclosed herein,individually, as well as groups of one or more compound species. Thescope of this invention includes any combination of these group andsubstituent group definitions.

In one embodiment of this invention, R¹ is a fluoro-alkyl groupcontaining at least 2 fluoro groups (atoms). In another embodiment, R¹is a (C₁-C₂)alkyl group containing at least 2 fluoro groups. In aspecific embodiment, R¹ is CHF₂ or CF₃; more specifically, R¹ is CF₃

In selected embodiments, when Y is a bond, X₁, X₂, and X₃, takentogether with the atoms to which they are attached, form an oxadiazolyl(X₁ is O, X₂ and X₃ are N), oxazolyl (X₁ is O, X₂ is CH, X₃ is N),imidazolyl (X₁ is N or NH, X₂ is CH, X₃ is N or NH); or a triazolyl (X₁is N or NH, X₂ is N, X₃ is N or NH) ring moiety. In specificembodiments, when Y is a bond, X₁, X₂, and X₃, taken together with theatoms to which they are attached form an oxadiazolyl ring moiety.

In selected embodiments, when Y is —C(O)—, X₁, X₂, and X₃, takentogether with the atoms to which they are attached, form an thiazolyl(X₃ is S, X₁ is CH and X₂ is N or X₃ is S, X₁ is N and X₂ is CH),oxazolyl (X₃ is O, X₁ is CH and X₂ is N or X₃ is O, X₁ is N and X₂ isCH), thienyl (X₁ and X₂ are CH, X₃ is S) or furanyl (X₁ and X₂ are CH,X₃ is O) ring moiety. In specific embodiments, when Y is —C(O)—, X₁, X₂,and X₃, taken together with the atoms to which they are attached form athienyl, thiazolyl or oxazolyl ring moiety, more specifically a thienylmoiety.

In selected embodiments, when Y is —C(O)—, X₁, X₂, and X₃, takentogether with the atoms to which they are attached, form a furanyl orfuryl (X₁ is O, X₂ and X₃ are CH), oxazolyl (X₁ is O, X₂ is CH, and X₃is N), isoxazolyl (X₁ is O, X₂ is N, and X₃ is CH), or oxadiazolyl (X₁is O, X₂ and X₃ are N) ring moiety. In specific embodiments, when Y is—C(O)—, X₁, X₂, and X₃, taken together with the atoms to which they areattached form a furanyl (furyl) ring moiety.

The invention is further directed to a compound of Formula (I-a):

wherein R¹, R², R³, R⁴, A, Z, n and L are as defined herein.

The invention is still further directed to a compound of Formula (I-b):

wherein R¹, R², R³, R⁴, A, Z, n and L are as defined herein.

The invention is further directed to a compound of Formula (I-c), (I-d)or (I-e):

wherein R¹, R², R³, R⁴, A, Z, n and L are as defined herein.

The invention is still further directed to a compound of Formula (I-f),(I-g), (I-h), (I-i) or (I-j):

wherein R¹, R², R³, R⁴, A, Z, n and L are as defined herein.

The invention is still further directed to a compound of Formula (I-k),(I-l), (I-m), or (I-n):

wherein R¹, R², R³, R⁴, A, n and L are as defined herein.

In another embodiment, A is a phenyl group optionally substituted by 1-2groups independently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A). In further embodiments, A is a phenyl groupoptionally substituted by 1 group selected from methyl, ethyl, fluoro,chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano,—NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A), where each R^(A) isindependently H or methyl. In specific embodiments, A is anunsubstituted phenyl group or a phenyl group substituted by an ethyl,fluoro, cyano or methoxy group.

In yet another embodiment, A is a cyclopropyl, cyclopentyl or cyclohexylgroup, optionally substituted by 1-2 groups independently selected from(C₁-C₄)alkyl, (C₁-C₄)alkoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A). In further embodiments, A is a cyclopropyl,cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groupsindependently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy,—NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A), where each R^(A) isindependently H or methyl. In selected embodiments of this invention, Ais a cyclopropyl, cyclopentyl or cyclohexyl group.

In another embodiment of this invention, A is naphthyl, optionallysubstituted by 1-2 groups independently selected from (C₁-C₄)alkyl,halogen, cyano, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,—NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A).

In another embodiment of this invention, A is a 4-7 memberedheterocycloalkyl group optionally substituted by 1-3 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, oxo, —NR^(A)R^(A)and —((C₁-C₄)alkyl)NR^(A)R^(A).

In another embodiment of this invention, A is a 9-10 membered heteroaryloptionally substituted by 1-2 groups independently selected from(C₁-C₄)alkyl, halogen, cyano, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, oxo, —NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A). Inselected embodiments, A is isoquinolyl, indazolyl,tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl.

In further embodiments, A is a 5-6 membered heteroaryl optionallysubstituted by 1-2 groups independently selected from (C₁-C₄)alkyl,halogen, cyano, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,—NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A). In still furtherembodiments, A is a 5-6 membered heteroaryl optionally substituted by 1group selected from methyl, ethyl, fluoro, trifluoromethyl, —NR^(A)R^(A)and —((C₁-C₄)alkyl)NR^(A)R^(A), where each R^(A) is independently H ormethyl and the 5-6 membered heteroaryl contains 1 ring heteroatomselected form N, O and S and optionally contains 1 additional ringnitrogen atom. In selected embodiments, A is oxazolyl, pyrazolyl, orthienyl optionally substituted by a methyl group. In other selectedembodiments, A is pyrazolyl or thienyl, optionally substituted by amethyl group. In specific embodiments, A is thienyl. In other specificembodiments, A is oxazolyl.

In yet other embodiments, A is a pyridyl or pyridyl-N-oxide groupoptionally substituted by 1-2 groups independently selected from(C₁-C₄)alkyl, halogen, cyano, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, —NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A). Infurther embodiments, A is a pyridyl or pyridyl-N-oxide group optionallysubstituted by 1 group selected from methyl, ethyl, fluoro, chloro,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, —NR^(A)R^(A)and —((C₁-C₄)alkyl)NR^(A)R^(A), where each R^(A) is independently H ormethyl. In selected embodiments, A is pyridyl or pyridyl-N-oxide. Inspecific embodiments, A is pyridyl.

In another embodiment of this invention, Z is —C(═O)NR^(X)—,—NR^(X)C(═O)NR^(X), or —NR^(X)C(═O)—; particularly —C(═O)NR^(X)- or—NR^(X)C(═O)—. In another embodiment of this invention, Z is —SO₂NR^(X)-or —NR^(X)SO₂—. In another embodiment of this invention, Z is—NHCH(CF₃)— or —CH(CF₃)NH—. In another embodiment of this invention, Zis —CH(CF₃)— or —(C₁-C₄)alkyl-. In another embodiment of this invention,Z is —NR^(X)- or —(C₁-C₃)alkyl-NR^(X)—.

For each of the above embodiments of Z, R^(X), or for—NR^(X)C(═O)NR^(X), each R^(X), may be independently selected from H,(C₁-C₄)alkyl, and optionally substituted (C₂-C₄)alkyl, where saidoptionally substituted (C₂-C₄)alkyl is optionally substituted byhydroxyl, cyano, amino, (C₁-C₄)alkoxy, (C₁-C₄)alkyl)NH—, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)N—. For each of the above embodiments of Z,R^(X), or for —NR^(X)C(═O)NR^(X), each R^(X), may be independentlyselected from H, methyl, ethyl, tert-butyl, hydroxyethyl-,methoxymethyl-, cyanoethyl-, N-methylaminoethyl- anddimethylaminoethyl-. In specific embodiments, each R^(X) isindependently H, methyl or cyanoethyl, more specifically, R^(X) is H ormethyl.

In particular embodiments, Z is —C(═O)NR^(X)—, —SO₂—, —SO₂NR^(X)—,—CH(CF₃)NH—, methyl (methylenyl), ethyl (ethylenyl), —NR^(X)—, or—(C₁-C₃)alkyl-NR^(X)—, where each R^(X) is independently H, methyl orethyl. In specific embodiments, each R^(X) is H. In selectedembodiments, Z is —C(═O)NH—, —SO₂NH—, —CH(CF₃)NH—, ethyl (ethylenyl),—CH₂NH—, —CH₂N(CH₂CH₃)—, —CH(CH₃)N(CH₂CH₃)—, or —CH(CH₃)NH—. In specificembodiments, Z is —C(═O)NH— or —CH₂NH—.

In another embodiment of this invention, n is 0-4; particularly 0-3. Inspecific embodiments, n is 1 or n is O.

In another embodiment, one of R² and R³ is other than hydrogen. In yetanother embodiment, both R² and R³ are C₁₋₄ alkyl (e.g., methyl). In astill further embodiment, one of R² and R³ is H and the other of R² andR³ is C₁₋₄ alkyl (e.g., methyl). In a further embodiment, R² and R³taken together with the atom to which they are connected form anoptionally substituted 4, 5, or 6 membered cycloalkyl orheterocycloalkyl group, wherein said heterocycloalkyl group contains 1heteroatom selected from N, O and S and said optionally substitutedcycloalkyl or heterocycloalkyl group is optionally substituted by asubstituent selected from (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, halogen,cyano, aryl(C₁-C₂)alkyl-, (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-,—NR^(Ya)R^(Yb), —C(═O)OR^(Ya), —C(═O)NR^(Ya)R^(Yb), —NR^(Yb)C(═O)R^(Ya),—SO₂NR^(Ya)R^(Yb), and —NR^(Yb)SO₂R^(Ya), where R^(Ya) is selected fromH, (C₁-C₄)alkyl, phenyl(C₁-C₂)alkyl- and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-,and each R^(Yb) is independently selected from H and (C₁-C₄)alkyl,specifically H and methyl.

In another embodiment of this invention, when n is 0, R² and R³ areindependently selected from H and optionally substituted (C₁-C₄)alkyl,phenyl(C₁-C₂)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-.

In another embodiment, when n is 1, R² and R³ are independently selectedfrom H and optionally substituted (C₁-C₄)alkyl, phenyl(C₁-C₂)alkyl-, and(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-.

In another embodiment, when n is 1, R² is F and R³ is H, then Z is—C(═O)NH—, —NHC(═O)NH, —SO₂NH—, —NHCH(CF₃)—, —CH(CF₃)NH—, —CH(CF₃)—,—(C₁-C₄)alkyl-, —NH—, or —CH₂NH—; more specifically, Z is —C(═O)NH— or—CH₂NH—.

In another embodiment, when n is 2-4, R² and R³ are independentlyselected from H, fluoro, and optionally substituted (C₁-C₄)alkyl,phenyl(C₁-C₄)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₄)alkyl-.

In another embodiment of this invention, when n is 1-4, R² is selectedfrom amino, (C₁-C₄)alkylamino, ((C₁-C₃)alkyl)((C₁-C₃)alkyl)amino,amino(C₁-C₄)alkyl, (C₁-C₃)alkylamino(C₁-C₄)alkyl,((C₁-C₃)alkyl)((C₁-C₃)alkyl)amino(C₁-C₄)alkyl,(substituted(C₁-C₃)alkyl)((C₁-C₃)alkyl)amino(C₁-C₄)alkyl (where said(substituted (C₁-C₃)alkyl moiety is substituted by —C(═O)OH,—C(═O)O(C₁-C₄)alkyl, or 1-8 fluoro groups), aminocarbonyl(C₁-C₄)alkyl,(C₁-C₃)alkylaminocarbonyl(C₁-C₄)alkyl,((C₁-C₃)alkyl)((C₁-C₃)alkyl)aminocarbonyl(C₁-C₄)alkyl, hydroxyl,hydroxy(C₁-C₄)alkyl-, (C₁-C₄)alkoxy, and (C₁-C₄)alkoxy(C₁-C₄)alkyl- andR³ is selected from H and optionally substituted (C₁-C₄)alkyl,aryl(C₁-C₄)alkyl-, and (C₃-C₇)cycloalkyl(C₁-C₄)alkyl-.

In another embodiment of this invention, when n is 1-4, R² is selectedfrom amino, hydroxyl, and (C₁-C₄)alkoxy, and R³ is selected from H andoptionally substituted (C₁-C₄)alkyl, phenyl(C₁-C₂)alkyl-, and(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-. In another embodiment, n is 1-3, R² ishydroxyl and R³ is H or methyl; more specifically, n is 1, R² ishydroxyl and R³ is H or methyl. In another embodiment of this invention,(for any value of n) R² and R³ are independently selected from H andoptionally substituted (C₁-C₄)alkyl, phenyl(C₁-C₂)alkyl-, and(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-.

In another embodiment of this invention, (for any value of n) R² isselected from H and optionally substituted (C₁-C₄)alkyl,phenyl(C₁-C₂)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl- and R³ isselected from H and methyl.

In specific embodiments of this invention (for any value of n), R² andR³ are independently selected from H and methyl. In more specificembodiments, both R² and R³ are H or both R² and R³ are methyl.

In another embodiment of this invention, the aryl, phenyl, cycloalkyland each of the (C₁-C₄)alkyl or (C₁-C₂)alkyl moieties of said optionallysubstituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, phenyl (C₁-C₄)alkyl-,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl- and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl- of anyR² and R³ are optionally substituted by 1, 2 or 3 halogen (specificallyfluorine) groups and/or 1 or 2 groups independently selected from cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,NR^(A)R^(A), —((C₁-C₄)alkyl)NR^(A)R^(A), and hydroxyl.

In another embodiment of this invention, R² and R³ taken together withthe atom to which they are connected form an optionally substituted 4,5, or 6 membered cycloalkyl or heterocycloalkyl group, wherein saidheterocycloalkyl group contains 1 heteroatom selected from N, O and Sand said optionally substituted cycloalkyl or heterocycloalkyl group isoptionally substituted by a substituent selected from (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, halogen, cyano, aryl(C₁-C₂)alkyl-,(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-, —OR^(Ya), —NR^(Ya)R^(Yb), —C(═O)OR^(Ya),—C(═O)NR^(Ya)R^(Yb), —NR^(Yb)C(═O)R^(Ya), —SO₂NR^(Ya)R^(Yb), and—NR^(Yb)SO₂R^(Ya), where R^(Ya) is selected from H, (C₁-C₄)alkylphenyl(C₁-C₂)alkyl- and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-, and each R^(Yb)is independently selected from H and (C₁-C₄)alkyl, specifically H andmethyl.

In specific embodiments of this invention, R² and R³ taken together withthe atom to which they are connected form an optionally substituted 4, 5or 6 membered cycloalkyl or heterocycloalkyl group, wherein saidheterocycloalkyl group contains 1 heteroatom selected from N and O andsaid optionally substituted cycloalkyl or heterocycloalkyl group isoptionally substituted by a substituent selected from (C₁-C₄)alkyl,aryl(C₁-C₂)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-.

In selected embodiments of this invention, R² and R³ taken together withthe atom to which they are connected form a tetrahydropyranyl,2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl,cyclopropyl, cyclohexyl, 1-ethyl-piperidinyl, tetrahydrofuranyl,piperidinyl, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl,1-cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl,1-methyl-azetidinyl, 1-benzyl-azetidinyl, or1-cyclopropylmethyl-azetidinyl group.

In specific embodiments of this invention, R² and R³ taken together withthe atom to which they are connected form a tetrahydropyranyl,2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl group.

In another embodiment of this invention, L is 5-6 membered heteroaryl orphenyl which is substituted by R⁴ and is optionally further substituted,wherein when L is further substituted, L is substituted by 1 or 2substituents independently selected from halogen, cyano and methyl.

In another embodiment of this invention, L is a 5-membered heteroaryl,pyridyl or phenyl which is substituted by R⁴ and is optionally furthersubstituted, wherein when L is further substituted, L is substituted by1 substituent selected from chloro, fluoro, cyano and methyl.

In selected embodiments, L is pyrazolyl, oxadiazolyl,1-methyl-imidazolyl, thiazolyl, thienyl, triazolyl, pyridyl, phenyl,oxazolyl or isoxazolyl, any of which is substituted by a methyl group.

In specific embodiments, L is thiazolyl, thienyl, triazolyl, pyridyl,phenyl, or oxazolyl, any of which is substituted by a methyl group.

In another embodiment of this invention, R⁴ is H, halogen, (C₁-C₄)alkyl,halo(C₁-C₂)alkyl, (C₁-C₂)alkoxy,((C₁-C₂)alkyl)((C₁-C₂)alkyl)N(C₁-C₃)alkoxy-,((C₁-C₂)alkyl)((C₁-C₂)alkyl)N(C₁-C₃)alkyl-, (C₁-C₂)haloalkyl,(C₁-C₃)alkylamino, optionally substituted (C₃-C₆)cycloalkyl, optionallysubstituted phenyl, optionally substituted 5-6 memberedheterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,where said optionally substituted cycloalkyl, phenyl, heterocycloalkylor heteroaryl is optionally substituted by 1 or 2 groups independentlyselected from (C₁-C₄)alkyl, halogen, cyano, halo(C₁-C₂)alkyl,(C₁-C₂)alkoxy, halo(C₁-C₂)alkoxy, hydroxyl, —NR^(A)R^(C) and—((C₁-C₄)alkyl)NR^(A)R^(C).

In a selected embodiments, R⁴ is H, methyl, bromo, trifluoromethyl,dimethylaminoethoxy-, dimethylaminopropyl-, and optionally substitutedpyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, orphenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl,imidazolyl, thienyl, or phenyl are optionally substituted by 1-2substituents independently selected from methyl, chloro, bromo, fluoro,trifluoromethyl, methoxy, and cyano.

In a selected embodiments, R⁴ is H, methyl, bromo, trifluoromethyl,dimethylaminoethoxy-, phenyl, 4-chlorophenyl,2-bromophenyl-,4-fluorophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl,4-methoxyphenyl, cyclohexyl, imidazolyl, thienyl, pyrid-2-yl,pyrid-3-yl, or pyrid-4-yl.

In other embodiments of this invention, L-R⁴, taken together, form a1,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl,2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, benzimidazolyl,benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinylgroup, optionally substituted with 1 or 2 groups independently selectedfrom methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl,and morpholinylpropyl-.

In selected embodiments of this invention, L-R⁴, taken together, form a1,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group.

In another embodiment of this invention, each R^(A) and R^(C) isindependently selected from H and (C₁-C₄)alkyl; specifically each R^(A)and R^(C) is independently selected from H, methyl and ethyl.

In another embodiment of this invention, each R^(Y) is independentlyselected from H, (C₁-C₄)alkyl, phenyl, and —(C₁-C₄)alkylphenyl;specifically each R^(Y) is independently selected from H, methyl, ethyl,phenyl, benzyl and -ethylphenyl.

As used herein, the term “alkyl” represents a saturated, straight orbranched hydrocarbon moiety, which may be unsubstituted or substitutedby one, or more of the substituents defined herein. Exemplary alkylsinclude, but are not limited to methyl (Me), ethyl (Et), n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl(3-methyl-butyl), neo-pentyl(2,2-dimethylpropyl), etc. The term “C₁-C₄”refers to an alkyl containing from 1 to 4 carbon atoms.

When the term “alkyl” is used in combination with other substituentgroups, such as “haloalkyl” or “cycloalkyl-alkyl” or “arylalkyl”, theterm “alkyl” is intended to encompass a divalent straight orbranched-chain hydrocarbon radical. For example, “arylalkyl” is intendedto mean the radical -alkylaryl, wherein the alkyl moiety thereof is adivalent straight or branched-chain carbon radical and the aryl moietythereof is as defined herein, and is represented by the bondingarrangement present in a benzyl group (—CH₂-phenyl).

In addition, the term “alkyl” may be used to define a divalentsubstituent, such as a group bonded to two other groups. In thisinstance, the term “alkyl” is intended to encompass a divalent straightor branched-chain hydrocarbon radical. For example, “pentyl” is intendedto represent a pentylene diradical—wherein the pentyl moiety is any oneof a divalent straight (—CH₂CH₂CH₂CH₂CH₂—) or branched(—CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₂CH₃)—, —CH₂CH₂C(CH₃)₂—) chain 5-carbonradical.

As used herein, the term “cycloalkyl” refers to a non-aromatic,saturated, cyclic hydrocarbon ring. The term “(C₃-C₈)cycloalkyl” refersto a non-aromatic cyclic hydrocarbon ring having from three to eightring carbon atoms. Exemplary “(C₃-C₈)cycloalkyl” groups useful in thepresent invention include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

“Alkoxy” refers to a group containing an alkyl radical attached throughan oxygen linking atom. The term “(C₁-C₄)alkoxy” refers to a straight-or branched-chain hydrocarbon radical having at least 1 and up to 4carbon atoms attached through an oxygen linking atom. Exemplary“(C₁-C₄)alkoxy” groups useful in the present invention include, but arenot limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,s-butoxy, and t-butoxy.

“Aryl” represents a group or moiety comprising an aromatic, monovalentmonocyclic or bicyclic hydrocarbon radical containing from 6 to 10carbon ring atoms, which may be unsubstituted or substituted by one ormore of the substituents defined herein, and to which may be fused oneor more cycloalkyl rings, which may be unsubstituted or substituted byone or more substituents defined herein.

Generally, in the compounds of this invention, aryl is phenyl.

Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.“Heterocycloalkyl” represents a group or moiety comprising a stable,non-aromatic, monovalent monocyclic or bicyclic radical, which issaturated or partially unsaturated, containing 3 to 10 ring atoms, whichincludes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur,and which may be unsubstituted or substituted by one or more of thesubstituents defined herein. The heterocycloalkyl may be attached by anyatom of the monocyclic or bicyclic radical which results in the creationof a stable structure. This term encompasses bicyclic heterocycloalkylmoieties where the rings are joined at two atoms per ring, asexemplified by the bonding arrangement in 2,5-diazabicyclo[2.2.1]heptyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,7-oxa-2-azabicyclo[2.2.1]heptyl, 2-thia-5-azabicyclo[2.2.1]heptyl,7-azabicyclo[2.2.1]heptyl, 2,6-diazatricyclo[3.3.1.13,7]decyl,2-azatricyclo[3.3.1.13,7]decyl, 2,4,9-triazatricyclo[3.3.1.13,7]decyl,8-azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl,8-azabicyclo[3.2.1]octyl, octahydro-1H-pyrrolo[3,2-b]pyridyl group. Thisterm specifically excludes bicyclic heterocycloalkyl moieties where therings are joined at a single atom per ring (spiro), as exemplified bythe bonding arrangement in a 1-oxa-2-azaspiro[4.5]dec-2-en-3-yl group.Illustrative examples of heterocycloalkyls include, but are not limitedto, azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl,morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl (ortetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl,tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl,azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl,oxabicylo[2.2.1]heptyl and 1,5,9-triazacyclododecyl.

Generally, in the compounds of this invention, heterocycloalkyl groupsare 5-membered and/or 6-membered heterocycloalkyl groups, such aspyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl),tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl or pyrazolinyl,piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl,dihydropyranyl, 1,3-dioxanyl, tetrahydro-2H-1,4-thiazinyl, 1,4-dioxanyl,1,3-oxathianyl, and 1,3-dithianyl.

“Heteroaryl” represents a group or moiety comprising an aromaticmonovalent monocyclic or bicyclic radical, containing 5 to 10 ringatoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur, which may be unsubstituted or substituted by one or more of thesubstituents defined herein. This term also encompasses bicyclicheterocyclic-aryl compounds containing an aryl ring moiety fused to aheterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may beunsubstituted or substituted by one or more of the substituents definedherein. This term is also intended to encompass heterocyclic groupscontaining nitrogen and/or sulfur where the nitrogen or sulfurheteroatoms are optionally oxidized. Illustrative examples ofheteroaryls include, but are not limited to, thienyl, pyrrolyl,imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl,isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl),pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl,2,3-dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl,indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthridinyl, quinzolinyl, benzothiazolyl, benzimidazolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, indolinyl,cinnolinyl, pteridinyl, isothiazolyl.

Some of the heteroaryl groups present in the compounds of this inventionare 5-6 membered monocyclic heteroaryl groups. Selected 5-memberedheteroaryl groups contain one nitrogen, oxygen or sulfur ringheteroatom, and optionally contain 1, 2 or 3 additional nitrogen ringatoms. Selected 6-membered heteroaryl groups contain 1, 2, 3 or 4nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groupsinclude thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl,furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, andtetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyland thiadiazolyl.

Some of the heteroaryl groups present in the compounds of this inventionare 9-10 membered bicyclic heteroaryl groups. Selected 9-memberedheteroaryl groups contain one nitrogen, oxygen or sulfur ringheteroatom, and optionally contain 1, 2 or 3 additional nitrogen ringatoms. Selected 10-membered heteroaryl groups contain one nitrogen,oxygen or sulfur ring heteroatom, and optionally contain 1, 2, 3 or 4additional nitrogen ring atoms. Selected 9-10 membered heteroaryl groupsinclude benzo[b]thienyl, isobenzofuryl, 2,3-dihydrobenzofuryl,chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl,quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl,cinnolinyl, pteridinyl.

The terms “halogen” and “halo” represent chloro, fluoro, bromo or iodosubstituents. “Hydroxy” or “hydroxyl” is intended to mean the radical—OH. The term “oxo” is intended to mean a keto diradical (═O), such aspresent on a pyrrolidin-2-one ring.

The compounds of the invention are only those which are contemplated tobe “chemically stable” as will be appreciated by those skilled in theart.

Specifically, the invention is directed to a compound according toFormula (I-a):

wherein:

R¹ is —CF₃;

A is optionally substituted (C₃-C₆)cycloalkyl, phenyl, naphthyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 memberedheteroaryl, wherein any optionally substituted cycloalkyl, phenyl,naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by1-3 groups independently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A);

Z is —C(═O)NR^(X)—, —NR^(X)C(═O)NR^(X), —NR^(X)C(═O)—, —SO₂—,—SO₂NR^(X)—, —NR″ SO₂—, —NHCH(CF₃)—, —CH(CF₃)NH—, —CH(CF₃)—,—(C₁-C₄)alkyl-, —NR^(X)—, or —(C₁-C₃)alkyl-NR^(X)—;

n is 0-4;

when n is 0, R² and R³ are independently selected from H and optionallysubstituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-,

when n is 1-4, R² and R³ are independently selected from H, fluoro, andoptionally substituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, wherein, when n is 1, R² is F and R³ isH, then Z is —C(═O)NR^(X)—, —NR^(X)C(═O)NR^(X), —SO₂NR^(X)—,—NHCH(CF₃)—, —CH(CF₃)NH—, —CH(CF₃)—, —(C₁-C₄)alkyl-, —NR^(X)—, or—(C₁-C₃)alkyl-NR^(X)—, and

when n is 1-4, R² is selected from amino, hydroxyl, and (C₁-C₄)alkoxy,and R³ is selected from H and optionally substituted (C₁-C₄)alkyl,aryl(C₁-C₄)alkyl-, and (C₃-C₇)cycloalkyl(C₁-C₄)alkyl-,

wherein the aryl, cycloalkyl and each of the (C₁-C₄)alkyl moieties ofsaid optionally substituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl- of any R² and R³ are optionallysubstituted by 1, 2 or 3 groups independently selected from halogen,cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,halogen, —NR^(A)R^(A), —((C₁-C₄)alkyl)NR^(A)R^(A), (C₁-C₄)alkoxy,hydroxyl, cyano, halo(C₁-C₄)alkyl, and halo(C₁-C₄)alkoxy;

or R² and R³ taken together with the atom to which they are connectedform an optionally substituted 4, 5, 6, or 7 membered cycloalkyl orheterocycloalkyl group, wherein said heterocycloalkyl group contains 1or 2 heteroatoms independently selected from N, O and S and saidoptionally substituted cycloalkyl or heterocycloalkyl group isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, halogen, cyano, aryl(C₁-C₄)alkyl-,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, —OR^(Y), —NR^(Y)R^(Y), —C(═O)OR^(Y),—C(═O)NR^(Y)R^(Y), —NR^(Y)C(═O)R^(Y), —SO₂NR^(Y)R^(Y), —NR^(Y)SO₂R^(Y),—OC(═O)NR^(Y)R^(Y), —NR^(Y)C(═O)OR^(Y), and —NR^(Y)C(═O)NR^(Y)R^(Y); and

L is 5-6 membered heteroaryl or phenyl which is substituted by R⁴ and isoptionally further substituted,

wherein when L is further substituted, L is substituted by 1 or 2substituents independently selected from halogen, cyano and(C₁-C₄)alkyl;

R⁴ is H, (C₁-C₄)alkyl, halo, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkoxy,((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkyl-, (C₁-C₄)haloalkoxy-,(C₁-C₄)alkylamino, optionally substituted (C₃-C₆)cycloalkyl, optionallysubstituted phenyl, optionally substituted 5-6 memberedheterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,

wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkylor heteroaryl is optionally substituted by 1, 2 or 3 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio-, halo(C₁-C₄)alkoxy,hydroxyl, —NR^(A)R^(C) and —((C₁-C₄)alkyl)NR^(A)R^(C);

or L-R⁴, taken together, form a 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl orisoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl orisoindolinyl group is optionally substituted by 1, 2 or 3 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio-, halo(C₁-C₄)alkoxy,hydroxyl, —NR^(A)R^(C) and —((C₁-C₄)alkyl)NR^(A)R^(C);

wherein each R^(A) is independently selected from H and (C₁-C₄)alkyl;

R^(C) is H, (C₁-C₄)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6membered heteroaryl, or R^(A) and R^(C) taken together with the atom towhich they are attached form an optionally substituted 4-8 memberedheterocyclic ring, optionally containing one additional heteroatomselected from N, O and S;

each R^(X) is independently selected from H, (C₁-C₆)alkyl, andoptionally substituted (C₂-C₆)alkyl, where said optionally substituted(C₂-C₆)alkyl is optionally substituted by hydroxyl, cyano, amino,(C₁-C₄)alkoxy, (C₁-C₄)alkyl)NH—, or ((C₁-C₄)alkyl)((C₁-C₄)alkyl)N—; and

each R^(Y) is independently selected from H, (C₁-C₄)alkyl, phenyl, and—(C₁-C₄)alkylphenyl;

provided that the compound is not:

-   3-[4-(trifluoromethyl)phenyl]-N-{3-(trifluoromethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl}propanamido,-   3-{7-methyl-2-[4-(3-methyl-5-isoxazolyl)butyl]-1-benzofuran-5-yl}-5-(trifluoromethyl)-1,2,4-oxadiazole,-   1-[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,-   7-methyl-1-[4-(3-methyl-5-isoxazolyl)butyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,-   7-methyl-1-[5-(3-methyl-5-isoxazolyl)pentyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,-   7-methyl-1-[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indole,    or-   N-(phenylmethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

Accordingly, the invention is further directed to a compound accordingto Formula I, wherein:

R¹ is CHF₂ or CF₃;

Y is a bond, X₁ is O, and X₂ and X₃ are N, or

Y is —C(O)—, X₁ and X₂ are CH, and X₃ is S, or

Y is —C(O)—, X₁ is O, and X₂ and X₃ are CH;

A is a phenyl group optionally substituted by 1 group selected frommethyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, cyano, —NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A), or

A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionallysubstituted by 1-2 groups independently selected from methyl, ethyl,tert-butyl, methoxy, ethoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A), or

A is a 5-6 membered heteroaryl or a 9-10 membered heteroaryl optionallysubstituted by 1 group selected from methyl, ethyl, fluoro,trifluoromethyl, —NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A), where the5-6 membered heteroaryl or 9-10 membered heteroaryl contains 1 ringheteroatom selected form N, O and S and optionally contains 1 additionalring nitrogen atom,

where each R^(A) is independently H or methyl;

Z is —C(═O)NR^(X)—, —NR^(X)C(═O)NR^(X), —NR^(X)C(═O)—, —NHCH(CF₃)—,—CH(CF₃)NH—, —CH(CF₃)—, —(C₁-C₄)alkyl-, or —(C₁-C₄)alkylNR^(X)—, whereR^(X) is H, (C₁-C₄)alkyl, or optionally substituted (C₂-C₄)alkyl, wheresaid optionally substituted (C₂-C₄)alkyl is optionally substituted byhydroxyl, cyano, amino, (C₁-C₄)alkoxy, (C₁-C₄)alkyl)NH—, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)N—;

n is 0-3 and R² and R³ are independently selected from H and optionallysubstituted (C₁-C₄)alkyl, phenyl(C₁-C₂)alkyl-, and(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-, or

n is 1-3 and R² is hydroxyl and R³ is H or methyl, or

n is 0-3 and R² and R³ taken together with the atom to which they areconnected form an optionally substituted 4, 5, or 6 membered cycloalkylor heterocycloalkyl group, wherein said heterocycloalkyl group contains1 heteroatom selected from N, O and S and said optionally substitutedcycloalkyl or heterocycloalkyl group is optionally substituted by asubstituent selected from (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, halogen,cyano, aryl(C₁-C₂)alkyl-, (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-, —OR^(Ya),—NR^(Ya)R^(Yb), —C(═O)OR^(Ya), —C(═O)NR^(Ya)R^(Yb), —NR^(Yb)C(═O)R^(Ya),—SO₂NR^(Ya)R^(Yb), and —NR^(Yb)SO₂R^(Ya), where R^(Ya)is selected fromH, (C₁-C₄)alkyl phenyl(C₁-C₂)alkyl- and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-,and each R^(Yb) is independently selected from H and (C₁-C₄)alkyl;

L is 5-6 membered heteroaryl or phenyl which is substituted by R⁴ and isoptionally further substituted, wherein when L is further substituted, Lis substituted by 1 or 2 substituents independently selected fromhalogen, cyano and methyl; and

R⁴ is H, halogen, (C₁-C₄)alkyl, halo(C₁-C₂)alkyl, (C₁-C₂)alkoxy,((C₁-C₂)alkyl)((C₁-C₂)alkyl)N(C₁-C₃)alkoxy-,((C₁-C₂)alkyl)((C₁-C₂)alkyl)N(C₁-C₃)alkyl-, (C₁-C₂)haloalkyl,(C₁-C₃)alkylamino, optionally substituted (C₃-C₆)cycloalkyl, optionallysubstituted phenyl, optionally substituted 5-6 memberedheterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,where said optionally substituted cycloalkyl, phenyl, heterocycloalkylor heteroaryl is optionally substituted by 1 or 2 groups independentlyselected from (C₁-C₄)alkyl, halogen, cyano, halo(C₁-C₂)alkyl,(C₁-C₂)alkoxy, halo(C₁-C₂)alkoxy, hydroxyl, —NR^(A)R^(C) and—((C₁-C₄)alkyl)NR^(A)R^(C);

or a salt, particularly a pharmaceutically acceptable salt, thereof.

The invention is yet further directed to a compound as defined hereinwherein:

n is 0-3 and R² and R³ are independently selected from H and optionallysubstituted (C₁-C₄)alkyl, phenyl(C₁-C₂)alkyl-, and(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-, or

n is 1-3 and R² is hydroxyl and R³ is H or methyl, or

n is 0-3 and R² and R³ taken together with the atom to which they areconnected form an optionally substituted 4, 5 or 6 membered cycloalkylor heterocycloalkyl group, wherein said heterocycloalkyl group contains1 heteroatom selected from N and O and said optionally substitutedcycloalkyl or heterocycloalkyl group is optionally substituted by asubstituent selected from (C₁-C₄)alkyl, aryl(C₁-C₂)alkyl-, and(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-;

R^(X) is H, methyl or cyanoethyl;

L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted byR⁴ and is optionally further substituted, wherein when L is furthersubstituted, L is substituted by 1 substituent selected from chloro,fluoro, cyano and methyl; and

R⁴ is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-,dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl,piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where thepyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, orphenyl are optionally substituted by 1-2 substituents independentlyselected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy,and cyano;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

The invention is specifically directed to a compound according toFormula I, wherein:

R¹ is CHF₂ or CF₃;

Y is a bond, X₁ is O, and X₂ and X₃ are N, or

Y is —C(O)—, X₁ and X₂ are CH, and X₃ is S, or

Y is —C(O)—, X₁ is O, and X₂ and X₃ are CH;

A is an unsubstituted phenyl group or a phenyl group substituted by anethyl, fluoro, cyano or methoxy group, or a thienyl, pyridyl,cyclopropyl, cyclopentyl or cyclohexyl group;

Z is —C(═O)NH— or —CH₂NH—;

n is 0 or 1 and both R² and R³ are H or both R² and R³ are methyl, or

n is 1 and R² is hydroxyl and R³ is H or methyl, or

n is 0 or 1 and R² and R³ taken together with the atom to which they areconnected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl,cyclopentyl, 1-methyl-piperidinyl group;

L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any ofwhich is optionally substituted by a methyl group;

R⁴ is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl,4-chlorophenyl, 2-bromophenyl-, 4-fluorophenyl, 4-cyanophenyl,3-trifluoromethylphenyl, 4-methoxyphenyl, cyclohexyl, imidazolyl,thienyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; or

L-R⁴, taken together, form a 1,3-benzodioxolyl, tetrahydroisoquinolyl orisoindolinyl group;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

The invention is more specifically directed to a compound according toFormula I, wherein:

R¹ is CHF₂ or CF₃;

Y is a bond, X₁ is O, and X₂ and X₃ are N;

A is an unsubstituted phenyl or pyridyl group;

Z is —C(═O)NH— or —CH₂NH—;

n is 1;

R² and R³ are both methyl, or

R² is hydroxyl and R³ is methyl, or

R² and R³ are both hydrogen, or

R² is methyl and R³ is hydrogen, or

R² is hydroxyl and R³ is hydrogen, or

R² is dimethylamino and R³ is H, or

R² is N,N-dimethylaminoethyl and R³ is H, or

R² and R³ taken together with the atom to which they are connected forma tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, or a1-methyl-piperidinyl group;

L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any ofwhich is optionally substituted by a methyl group;

R⁴ is phenyl, optionally substituted by halo (chloro or fluoro), cyano,halo(C₁-C₂)alkyl, or (C₁-C₂)alkoxy;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

As used herein, the term “compound(s) of the invention” means a compoundof formula (I) (as defined above) in any form, i.e., any salt ornon-salt form (e.g., as a free acid or base form, or as apharmaceutically acceptable salt thereof) and any physical form thereof(e.g., including non-solid forms (e.g., liquid or semi-solid forms), andsolid forms (e.g., amorphous or crystalline forms, specific polymorphicforms, solvates, including hydrates (e.g., mono-, di- andhemi-hydrates)), and mixtures of various forms.

As used herein, the term “optionally substituted” means unsubstitutedgroups or rings (e.g., cycloalkyl, heterocycle, and heteroaryl rings)and groups or rings substituted with one or more specified substituents.

The compounds according to Formula I may contain one or more asymmetriccenter (also referred to as a chiral center) and may, therefore, existas individual enantiomers, diastereomers, or other stereoisomeric forms,or as mixtures thereof. Chiral centers, such as chiral carbon atoms, mayalso be present in a substituent such as an alkyl group. Where thestereochemistry of a chiral center present in Formula I, or in anychemical structure illustrated herein, is not specified the structure isintended to encompass all individual stereoisomers and all mixturesthereof. Thus, compounds according to Formula I containing one or morechiral centers may be used as racemic mixtures, scalemic mixtures, or asdiaseteromerically or enantiomerically pure materials.

Individual stereoisomers of a compound according to Formula I whichcontain one or more asymmetric center may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. The skilled artisan willappreciate that where the desired stereoisomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired form. Alternatively,specific stereoisomers may be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer to the other by asymmetric transformation.

When a disclosed compound or its salt is named or depicted by structure,it is to be understood that the compound or salt, including solvates(particularly, hydrates) thereof, may exist in crystalline forms,non-crystalline forms or a mixture thereof. The compound or salt, orsolvates (particularly, hydrates) thereof, may also exhibit polymorphism(i.e. the capacity to occur in different crystalline forms). Thesedifferent crystalline forms are typically known as “polymorphs.” It isto be understood that when named or depicted by structure, the disclosedcompound, or solvates (particularly, hydrates) thereof, also include allpolymorphs thereof. Polymorphs have the same chemical composition butdiffer in packing, geometrical arrangement, and other descriptiveproperties of the crystalline solid state. Polymorphs, therefore, mayhave different physical properties such as shape, density, hardness,deformability, stability, and dissolution properties. Polymorphstypically exhibit different melting points, IR spectra, and X-ray powderdiffraction patterns, which may be used for identification. One ofordinary skill in the art will appreciate that different polymorphs maybe produced, for example, by changing or adjusting the conditions usedin crystallizing/recrystallizing the compound.

Because of their potential use in medicine, the salts of the compoundsof Formula I are preferably pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts include those described by Berge,Bighley and Monkhouse, J. Pharm. Sci (1977) 66, pp 1-19. Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention.

Typically, a salt may be readily prepared by using a desired acid orbase as appropriate. The salt may precipitate from solution and becollected by filtration or may be recovered by evaporation of thesolvent.

When a compound of the invention is a base (contain a basic moiety), adesired salt form may be prepared by any suitable method known in theart, including treatment of the free base with an inorganic acid, suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, or with an organic acid, such as aceticacid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, and the like, or with a pyranosidyl acid, such asglucuronic acid or galacturonic acid, or with an alpha-hydroxy acid,such as citric acid or tartaric acid, or with an amino acid, such asaspartic acid or glutamic acid, or with an aromatic acid, such asbenzoic acid or cinnamic acid, or with a sulfonic acid, such asp-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or thelike.

Suitable addition salts are formed from acids which form non-toxic saltsand examples include acetate, p-aminobenzoate, ascorbate, aspartate,benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate,bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate,clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate,esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate,gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,dihydrochloride, hydrofumarate, hydrogen phosphate, hydroiodide,hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate,pamoate (embonate), palmate, palmitate, pantothenate,phosphate/diphosphate, pyruvate, polygalacturonate, propionate,saccharate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetateand valerate.

Other exemplary acid addition salts include pyrosulfate, sulfite,bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, suberate, sebacate,butyne-1,4-dioate, hexyne-1,6-dioate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,phenylacetate, phenylpropionate, phenylbutrate, lactate,γ-hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate,propanesulfonate, naphthalene-1-sulfonate and naphthalene-2-sulfonate.

If an inventive basic compound is isolated as a salt, the correspondingfree base form of that compound may be prepared by any suitable methodknown to the art, including treatment of the salt with an inorganic ororganic base, suitably an inorganic or organic base having a higherpK_(a) than the free base form of the compound.

When a compound of the invention is an acid (contains an acidic moiety),a desired salt may be prepared by any suitable method known to the art,including treatment of the free acid with an inorganic or organic base,such as an amine (primary, secondary, or tertiary), an alkali metal oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include organic salts derived from amino acids such asglycine and arginine, ammonia, primary, secondary, and tertiary amines,and cyclic amines, such as N-methyl-D-glucamine, diethylamine,isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine,ethanolamine, piperidine, morpholine, and piperazine, as well asinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum, and lithium.

Certain of the compounds of this invention may form salts with one ormore equivalents of an acid (if the compound contains a basic moiety) ora base (if the compound contains an acidic moiety). The presentinvention includes within its scope all possible stoichiometric andnon-stoichiometric salt forms.

Compounds of the invention having both a basic and acidic moiety may bein the form of zwitterions, acid-addition salt of the basic moiety orbase salts of the acidic moiety.

This invention also provides for the conversion of one pharmaceuticallyacceptable salt of a compound of this invention, e.g., a hydrochloridesalt, into another pharmaceutically acceptable salt of a compound ofthis invention, e.g., a sodium salt.

For solvates of the compounds of Formula I, or salts thereof that are incrystalline form, the skilled artisan will appreciate thatpharmaceutically-acceptable solvates may be formed wherein solventmolecules are incorporated into the crystalline lattice duringcrystallization. Solvates may involve nonaqueous solvents such asethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethylacetate, or they may involve water as the solvent that is incorporatedinto the crystalline lattice. Solvates wherein water is the solvent thatis incorporated into the crystalline lattice are typically referred toas “hydrates.” Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. The inventionincludes all such solvates.

The subject invention also includes isotopically-labeled compounds whichare identical to those recited in formula (I) but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number most commonly foundin nature. Examples of isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,fluorine, iodine and chlorine such as ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I or ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H or ¹⁴C have beenincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, ie. ³H, and carbon-14, ie. ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emissiontomography).

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

The compounds of Formula I may be obtained by using synthetic proceduresillustrated in the Schemes below or by drawing on the knowledge of askilled organic chemist. The synthesis provided in these Schemes areapplicable for producing compounds of the invention having a variety ofdifferent R¹ and R² groups employing appropriate precursors, which aresuitably protected if needed, to achieve compatibility with thereactions outlined herein. Subsequent deprotection, where needed,affords compounds of the nature generally disclosed. While the Schemesare shown with compounds only of Formula I, they are illustrative ofprocesses that may be used to make the compounds of the invention.

Intermediates (compounds used in the preparation of the compounds of theinvention) may also be present as salts. Thus, in reference tointermediates, the phrase “compound(s) of formula (number)” means acompound having that structural formula or a pharmaceutically acceptablesalt thereof.

Specific compounds of this invention include the compounds of Examples1-141.

Representative compounds of this invention include:

-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(4-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(4-(1H-imidazol-1-yl)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)methyl)benzamide,-   1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)methanamine,-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-((4-(4-phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((1-(4-phenylthiazol-2-yl)cyclopentyl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(3-phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(2-phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(4-methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-methyl-2-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((1-methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxamide,-   N-((4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   3-fluoro-N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   3-methoxy-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(4-cyanophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzenesulfonamide,-   3-ethyl-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(3-bromophenyl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide,-   N-(2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)cyclopropanecarboxamide,-   N-((1-methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinamide,-   N-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinamide,-   N-(2-(dimethylamino)-2-(4-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((1-(4-phenylthiazol-2-yl)cyclopropyl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   3-(4-(4-fluorophenyl)thiazol-2-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide,-   N-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-phenylthiazol-2-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-((4-(3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-methyl-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   2,2,2-trifluoro-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-1-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)ethanamine,-   N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(3-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(5-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(3-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-methyl-2-(5-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-((2-(4-fluorophenyl)oxazol-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine,-   3-(3-(4-(4-phenylthiazol-2-yl)butyl)phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N-(2-methyl-2-(5-phenyloxazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-phenylthiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-methyl-2-(2-phenylthiazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide,-   N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,-   2-fluoro-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxamide,-   N-(2-(1-methyl-2-phenyl-1H-imidazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methyl    propyl)nicotinamide,-   N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide    hydrochloride,-   N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-((4-(2-(4-chlorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine,-   N-(2-(2-(4-fluorophenyl)oxazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-methoxyphenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   2-chloro-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(2-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   3-(5-(2,2-difluoroacetyl)thiophen-2-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiazol-2-yl)benzamide,-   N-(2-(1-methyl-2-phenyl-1H-imidazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)furan-2-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(4-fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-([1,1′-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4′-fluoro-[1,1′-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-((4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(4-(3,5-difluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-phenyloxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-phenyloxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-methyl-2-(3-phenyl-1H-pyrazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-((4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(4-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)furan-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-3-yl)benzamide,-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)-1,2,4-oxadiazol-3-yl)benzamide,

and salts, particularly pharmaceutically acceptable salts, thereof.

Particular compounds of this invention include:

-   N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide,-   N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiazol-2-yl)benzamide,-   N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,-   (3-(5-(4-fluorophenyl)oxazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanone,

and salts, particularly pharmaceutically acceptable salts, thereof.

Compound names were generated using the software naming program ChemDraw11.0 available from CambridgeSoft Corporation., 100 CambridgePark Drive,Cambridge, Mass. 02140, USA (http://www.cambridgesoft.com).

The compounds of Formula I can be prepared according to the methodsoutlined below.

The invention also includes various deuterated forms of the compounds ofFormula I. Each available hydrogen atom attached to a carbon atom may beindependently replaced with a deuterium atom. A person of ordinary skillin the art will know how to synthesize deuterated forms of the compoundsof Formula I. For example, deuterated alkyl groups (e.g.,N-(deutero-methyl)amines) may be prepared by conventional techniques(see for example: methyl-d₃-amine available from Aldrich Chemical Co.,Milwaukee, Wis., Cat. No. 489,689-2). Employing such compounds willallow for the preparation of compounds of Formula I in which varioushydrogen atoms of the N-methyl groups are replaced with a deuteriumatom.

The present invention is directed to a method of inhibiting an HDACwhich comprises contacting the acetylase with a compound of Formula I ora salt thereof, particularly a pharmaceutically acceptable salt thereof.This invention is also directed to a method of treatment of anHDAC-mediated disease or disorder comprising administering atherapeutically effective amount of the compound of Formula I or a saltthereof, particularly a pharmaceutically acceptable salt thereof, to apatient, specifically a human, in need thereof. As used herein,“patient” refers to a mammal, specifically, a human. A therapeutically“effective amount” is intended to mean that amount of a compound that,when administered to a patient in need of such treatment, is sufficientto effect treatment, as defined herein. Thus, e.g., a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is a quantity of an inventive agent that, whenadministered to a human in need thereof, is sufficient to inhibit theactivity of HDAC such that a disease condition which is mediated by thatactivity is reduced, alleviated or prevented. The amount of a givencompound that will correspond to such an amount will vary depending uponfactors such as the particular compound (e.g., the potency (pXC₅₀),efficacy (EC₅₀), and the biological half-life of the particularcompound), disease condition and its severity, the identity (e.g., age,size and weight) of the patient in need of treatment, but cannevertheless be routinely determined by one skilled in the art.Likewise, the duration of treatment and the time period ofadministration (time period between dosages and the timing of thedosages, e.g., before/with/after meals) of the compound will varyaccording to the identity of the mammal in need of treatment (e.g.,weight), the particular compound and its properties (e.g.,pharmaceutical characteristics), disease or condition and its severityand the specific composition and method being used, but can neverthelessbe determined by one of skill in the art.

“Treating” or “treatment” is intended to mean at least the mitigation ofa disease condition in a patient, where the disease condition is causedor mediated by HDAC. The methods of treatment for mitigation of adisease condition include the use of the compounds in this invention inany conventionally acceptable manner, for example for prevention,retardation, prophylaxis, therapy or cure of a disease.

In one embodiment, this invention is directed to a method of treating,ameliorating, or preventing an autoimmune disorder, an immunologicaldisease, an inflammatory disorder, transplant/graft rejection (e.g.,allograft), lymphopenia, or graft-versus-host disease (GvHD) in apatient, specifically in a human, comprising administering to thepatient a compound of this invention, in an amount sufficient toincrease the level and/or activity of a Treg cell or a population ofTreg cells in the patient, thereby treating, ameliorating, or preventingthe autoimmune disorder, inflammatory disorder, transplant/graftrejection, lymphopenia, or GvHD in the patient.

Additional examples of diseases and conditions that may be treated bythe compounds of this invention include but not limited to type IIdiabetes mellitus, coronary artery disease, allergies and allergicreactions, and sepsis/toxic shock.

Exemplary autoimmune disorders include, but are not limited to, multiplesclerosis, juvenile idiopathic arthritis, psoriatic arthritis, hepatitisC virus-associated mixed cryoglobulinemia, polymyositis,dermatomyositis, polyglandular syndrome type II, autoimmune liverdisease, Kawasaki disease, myasthenia gravis, immunodysregulationpolyendocrinopathy enteropathy X-linked syndrome (IPEX (syndrome)), typeI diabetes, psoriasis, hypothyroidism, hemolytic anemia, autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy (APECED),thrombocytopenia, spondyloarthritis, Sjogren's syndrome, rheumatoidarthritis, inflammatory bowel disease (IBD), Crohn's disease, ulcerativecolitis, eczema, gastritis, or thyroiditis. As part of a nonlimitinglist, the inflammatory disorder can be contact hypersensitivity, atopicdermatitis or Still disease.

Additional examples of autoimmune diseases include but are not limitedto autoimmune diseases include osteoarthritis, systemic sclerosis,sarcoidosis, insulin dependent diabetes mellitus (IDDM, type Idiabetes), reactive arthritis, scleroderma, vasculitis, Wegener'sgranulomatosis, Hashimoto's disease, scleroderma, oophoritis, Lupus(SLE), Grave's disease, asthma, cryoglobulinemia, primary biliarysclerosis, pemphigus vulgaris, hemolytic anemia and pernicious anemia.

Examples of transplant/graft rejection (e.g., allograft), lymphopenia,or graft-versus-host disease (GvHD) are those arising from cell, tissueand organ transplantation procedures, such as therapeutic celltransplants such as stem cells, muscle cells such as cardiac cells,islet cells, liver cells, bone marrow transplants, skin grafts, bonegrafts, lung transplants, kidney transplants, liver transplants, andheart transplants.

Other examples of diseases and conditions that may be treated by thecompounds of this invention include but are not limited to cysticfibrosis, osteoporosis, obesity, epilepsy, depression, thalassemia,sickle cell anemia, amyotrophic lateral sclerosis (ALS) andhyperalgesia, cardiac disease (e.g., stroke, hypertension,atherothrombotic diseases, artherosclerosis or limitation of infarctsize in acute coronary syndrome), diseases or disorders involvingmuscular atrophy, gentamicin-induced hearing loss, drug resistance(e.g., drug resistance in osteosarcoma and colon cancer cells),infectious diseases, and immune deficiency/immunocompromised patients.Examples of infectious diseases relate to various pathogen infectionssuch as viral, fungal, bacterial, mycoplasm, and infections byunicellular and multicellular eukaryotic organisms. Common humanpathogens include but are not limited to HIV, HSV, HPV, Hepatitis A, Band C viruses, influenza, denge, zostrella, rubella, RSV, rotavirus,gram positive, gram negative, streptococcus, tetanus, staphalococcus,tuberculosis, listeria, and malaria.

In another embodiment, this invention is directed to inhibitors of HDACand their use to stop or reduce the growth of neoplastic cells, e.g.,cancer cells and tumor cells.

The growth of cancer cells and/or tumor cells that are found in thefollowing cancer types may be reduced by treatment with a compound ofthis invention: carcinoma (e.g., adenocarcinoma), heptaocellularcarcinoma, sarcoma, myeloma (e.g., multiple myeloma), treating bonedisease in multiple myeloma, leukemia, childhood acute lymphoblasticleukemia and lymphoma (e.g., cutaneous cell lymphoma), and mixed typesof cancers, such as adenosquamous carcinoma, mixed mesodermal tumor,carcinosarcoma, and teratocarcinoma.

In one aspect of the invention, breast or prostate cancers or tumors aretreated using the HDAC inhibitors of this invention.

Other cancers that may be treated using the compounds of this inventioninclude, but are not limited to, bladder cancer, breast cancer, prostatecancer, stomach cancer, lung cancer, colon cancer, rectal cancer,colorectal cancer, liver cancer, endometrial cancer, pancreatic cancer,cervical cancer, ovarian cancer; head and neck cancer, and melanoma.

The inhibitors of the invention may be employed alone or in combinationwith standard anti-cancer regimens for neoplastic cell, e.g., tumor andcancer, treatments.

The compounds of the invention may be administered by any suitable routeof administration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration, rectaladministration, and administration by inhalation. Parenteraladministration refers to routes of administration other than enteral,transdermal, or by inhalation, and is typically by injection orinfusion. Parenteral administration includes intravenous, intramuscular,and subcutaneous injection or infusion. Inhalation refers toadministration into the patient's lungs whether inhaled through themouth or through the nasal passages. Topical administration includesapplication to the skin.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution, andhalf-life, which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the conditionbeing treated, the severity of the condition being treated, the age andphysical condition of the patient being treated, the medical history ofthe patient to be treated, the nature of concurrent therapy, the desiredtherapeutic effect, and like factors within the knowledge and expertiseof the skilled artisan. It will be further understood by such skilledartisans that suitable dosing regimens may require adjustment given anindividual patient's response to the dosing regimen or over time asindividual patient needs change.

Treatment of HDAC-mediated disease conditions may be achieved using thecompounds of this invention as a monotherapy, or in dual or multiplecombination therapy, such as in combination with other agents, forexample, in combination with one or more of the following agents: DNAmethyltransferase inhibitors, acetyl transferase enhancers, proteasomeor HSP90 inhibitors, and one or more immunosuppressants that do notactivate the T suppressor cells including but are not limited tocorticosteroids, rapamycin, Azathioprine, Mycophenolate, Cyclosporine,Mercaptopurine (6-MP), basiliximab, daclizumab, sirolimus, tacrolimus,Muromonab-CD3, cyclophosphamide, and methotrexate, which areadministered in effective amounts as is known in the art.

The compounds of the invention will normally, but not necessarily, beformulated into a pharmaceutical composition prior to administration toa patient. Accordingly, in another aspect the invention is directed topharmaceutical compositions comprising a compound of the invention and apharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein an effective amount of a compound of theinvention can be extracted and then given to the patient such as withpowders, syrups, and solutions for injection. Alternatively, thepharmaceutical compositions of the invention may be prepared andpackaged in unit dosage form. For oral application, for example, one ormore tablets or capsules may be administered. A dose of thepharmaceutical composition contains at least a therapeutically effectiveamount of a compound of this invention (i.e., a compound of Formula I ora salt, particularly a pharmaceutically acceptable salt, thereof). Whenprepared in unit dosage form, the pharmaceutical compositions maycontain from 1 mg to 1000 mg of a compound of this invention.

The pharmaceutical compositions of the invention typically contain onecompound of the invention. However, in certain embodiments, thepharmaceutical compositions of the invention contain more than onecompound of the invention. In addition, the pharmaceutical compositionsof the invention may optionally further comprise one or more additionalpharmaceutically active compounds.

As used herein, “pharmaceutically-acceptable excipient” means amaterial, composition or vehicle involved in giving form or consistencyto the composition. Each excipient must be compatible with the otheringredients of the pharmaceutical composition when commingled such thatinteractions which would substantially reduce the efficacy of thecompound of the invention when administered to a patient andinteractions which would result in pharmaceutical compositions that arenot pharmaceutically-acceptable are avoided. In addition, each excipientmust of course be of sufficiently high purity to render itpharmaceutically-acceptable.

The compounds of the invention and the pharmaceutically-acceptableexcipient or excipients will typically be formulated into a dosage formadapted for administration to the patient by the desired route ofadministration. Conventional dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols and solutions;and (6) topical administration such as creams, ointments, lotions,solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically-acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting the compound or compounds ofthe invention once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anti-caking agents, humectants, chelating agents, plasticizers,viscosity increasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically-acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically-acceptable excipients and may be useful inselecting suitable pharmaceutically-acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising an effective amount of a compoundof the invention and a diluent or filler. Suitable diluents and fillersinclude lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g.corn starch, potato starch, and pre-gelatinized starch), cellulose andits derivatives (e.g. microcrystalline cellulose), calcium sulfate, anddibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch), gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

In the following experimental descriptions, the following abbreviationsmay be used:

Abbreviation Meaning AcOH acetic acid aq aqueous brine saturated aqueousNaCl CH₂Cl₂ methylene chloride CH₃CN or MeCN acetonitrile CH₃NH₂methylamine d day DMF N,N-dimethylformamide DMSO dimethylsulfoxide equivequivalents Et ethyl Et₃N triethylamine Et₂O diethyl ether EtOAc ethylacetate h, hr hour HCl hydrochloric acid i-Pr₂NEtN′,N′-diisopropylethylamine KOt-Bu potassium tert-butoxide LCMS liquidchromatography-mass spectroscopy Me methyl MeOH or CH₃OH methanol MgSO₄magnesium sulfate min minute MS mass spectrum w microwave NaBH₄ sodiumborohydride Na₂CO₃ sodium carbonate NaHCO₃ sodium bicarbonate NaOHsodium hydroxide Na₂SO₄ sodium sulfate NH₄Cl ammonium chlorideNiCl₂•6H₂O nickel (II) chloride hexahydrate NMP N-methyl-2-pyrrolidonePh phenyl rt room temperature satd saturated SCX strong cation exchangeSPE solid phase extraction TFA trifluoroacetic acid THF tetrahydrofurant_(R) retention time

Example 1 Step 1: 2-(4-Phenylthiazol-2-yl)acetonitrile

A mixture of 2-bromoacetophenone (2 g, 10 mmol) and 2-cyanothioacetamide(1 g, 10 mmol) in EtOH (25 mL) was heated to 80° C. for 4 h. Thereaction mixture was cooled to room temperature and poured into anaqueous ammonia solution (final pH was >7). The mixture was thenextracted with EtOAc and the organic layer was washed with H₂O andbrine. Solvent was removed under reduced pressure and the crude productwas purified by flash column chromatography (silica gel 230-400 mesh,eluent 8% EtOAc in petroleum ether) to afford2-(4-phenylthiazol-2-yl)acetonitrile (1.5 g, yield 75%) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.91 (m, 2H), 7.49 (s, 1H),7.27-7.48 (m, 3H), 4.19 (s, 2H). MS (ESI) m/z: Calculated for C₁₁H₈N₂S:200.04; found: 201.2 (M+H)⁺.

Step 2: 4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

A solution of 2-(4-phenylthiazol-2-yl)acetonitrile (0.84 g, 4.19 mmol)in THF (25 mL) was cooled to 0° C. NaH was added (0.5 g, 60% dispersionin oil) portionwise over 10 min. The resulting mixture was allowed towarm up to room temperature and stirred for 20 min. 2-Bromoethyl ether(1.58 mL, 12.5 mmol) was added dropwise. The reaction mixture wasfurther stirred at room temperature for 1 h and then quenched withsaturated NH₄Cl solution. The reaction mixture was diluted with EtOAcand the organic layer was washed with H₂O and brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel60-120 mesh, eluent 4-8% EtOAc in petroleum ether) to afford4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile (0.97 g,yield 85%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.91-7.94 (m,2H), 7.51 (s, 1H), 7.37-7.48 (m, 3H), 4.07-4.14 (m, 2H), 3.87-3.96 (m,2H), 2.32-2.43 (m, 4H). MS (ESI) m/z: Calculated for C₁₅H₁₄N₂OS: 270.08;found: 271.2 (M+H)⁺.

Step 3: (4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

To a suspension of LiAlH₄ (220 mg, 5.9 mmol) in dry THF (10 mL) wasadded a solution of4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile (400 mg, 1.47mmol) in dry THF (10 mL) at 0° C. The reaction mixture was stirred atroom temperature for 1 h and then quenched carefully with water anddiluted with EtOAc. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography (neutral alumina, eluent5% MeOH in CHCl₃) to afford(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (150 mg,yield 37%): ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.91 (m, 2H), 7.48 (s, 1H),7.33-7.46 (m, 3H), 3.89-3.93 (m, 2H), 3.63-3.69 (m, 2H), 3.03 (s, 2H),2.30-2.33 (m, 2H), 1.90-1.97 (m, 2H). MS (ESI) m/z: Calculated forC₁₈H₁₈N₂OS: 274.11; found: 275.2 (M+H)⁺.

Step 4: 3-(N′-Hydroxycarbamimidoyl)benzoic acid

8-Hydroxyquinoline (5 mg, 0.03 mmol) was added to a solution of3-cyanobenzoic acid (1 g, 6.8 mmol) in 50 mL ethanol. To this reactionmixture were added first hydroxylamine hydrochloric acid (950 mg, 13.6mmol) in water (8 mL) followed by sodium carbonate (1.2 g, 10.9 mmol) inwater (12 mL). The mixture was heated to reflux for 4 h. After removalof ethanol under reduced pressure, the residue was diluted with water,and the aqueous solution was acidified with 10% HCl to pH ˜3. The whiteprecipitate was filtrated, washed with water and acetone and then driedunder reduced pressure to afford compound3-(N′-hydroxycarbamimidoyl)benzoic acid (1 g, yield 82%): ¹H NMR (400MHz, CDCl₃) δ 13.03 (br s, 1H), 9.76 (s, 1H), 8.27-8.26 (m, 1H),7.95-7.89 (m, 2H), 7.53 (t, J=7.8 Hz, 1H), 5.94 (br s, 2H). MS (ESI)m/z: Calculated for C₈H₈N₂O₃: 180.05; found: 180.9 (M+H)⁺.

Step 5: 3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

A solution of compound 3-(M-hydroxycarbamimidoyl)benzoic acid (1 g, 5.6mmol) in anhydrous pyridine (15 mL) was cooled to 0° C. andtrifluoroacetic anhydride (2.3 mL, 16.7 mmol) was added dropwise. Thereaction mixture was slowly warmed to room temperature and furtherheated to 50° C. for 3 h. The reaction mixture was poured into ice-waterand adjusted to pH ˜4 by addition of 1.5N HCl. The product was extractedwith EtOAc and the solvent removed under reduced pressure. The crudeproduct was purified by column chromatography [silica gel 60-120 mesh,eluent: 10% EtOAc in petroleum ether] to afford3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (400 mg, yield28%): ¹H NMR (400 MHz, CDCl₃) δ 13.44 (br s, 1H), 8.56 (s, 1H), 8.30 (d,J=7.9 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H). MS (ESI)m/z: Calculated for C₁₀H₅F₃N₂O₃: 258.03; found: 257 (M−H)⁻.

Step 6:N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

A mixture of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid(52 mg, 0.202 mmole),(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (50 mg,0.184 mmole), and EDCI (38.5 mg, 0.202 mmole) in CH₂Cl₂ (2 ml) wasstirred at room temperature for 8 h. The reaction mixture was thendiluted with methylene chloride (10 ml), washed with water (5 ml), driedover MgSO₄ and concentrated under reduced pressure. The residue waspurified by ISCO (silica gel, elute: 2% methanol in CH₂Cl₂) to giveN-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamideas a white solid product (59 mg, 62% yield): ¹H NMR (CDCl₃, 500 MHz):8.49 (s, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.88 (d,J=8 Hz, 2H), 7.56-7.53 (m, 2H), 7.52 (s, 1H), 7.369-7.31 (m, 3H),3.97-3.93 (m, 2H), 3.91 (d, J=5.5 Hz, 2H), 3.77-3.74 (m, 2H), 2.36-2.28(m, 2H), 2.06-2.04 (m, 2H). MS (ESI) m/z: Calculated for C₂₅H₂₁F₃N₄O₃S:514.13; found: 515.1 (M+H)⁺.

Examples 2-6 were synthesized from3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid and readilyavailable amines in a similar manner as part of a screening collectionand characterized by LCMS and ¹H NMR.

Example No. Compound Structure Compound Name 2

N-(4-(2- (Dimethylamino)ethoxy)benzyl)-3- (5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide 3

N-(2-(2- (Dimethylamino)ethoxy)benzyl)-3- (5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide 4

N-(4-(1H-Imidazol-1-yl)benzyl)-3- (5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide 5

N-(2-Cyanoethyl)-N-(pyridin-3- ylmethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide 6

3-(5-(Trifluoromethyl)-1,2,4- oxadiazol-3-yl)-N-((4-(4-(trifluoromethyl)phenyl)tetrahydro- 2H-pyran-4-yl)methyl)benzamide

Example 7 (3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanol

Borane dimethyl sulfide complex (0.3 mL, 2.9 mmol) was added to astirred solution of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoicacid (0.5 g, 1.9 mmol) in dry THF (10 mL) at 0° C. The reaction mixturewas slowly warmed to room temperature and further heated to 50° C. for 4h. Reaction mixture was then carefully quenched with dry MeOH andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica 60-120 mesh, eluent 10-15% EtOAc inpetroleum ether) to get pure alcohol compound(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (190 mg,yield 41%): ¹H NMR (400 MHz, CDCl₃) δ 8.14 (m, 1H), 8.06 (d, J=7.5 Hz,1H), 7.61-7.51 (m, 2H), 4.81 (s, 2H)

3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde

A solution of compound3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (150 mg, 0.6mmol) in dry CH₂Cl₂ (10 mL) was purged with argon for 10 min andDess-Martin periodinane (0.39 g, 0.9 mmol) was added to the solution at0° C. The reaction mixture was allowed to come to room temperature andstirred for 5 h. The reaction mixture was then quenched with saturatedsodium thiosulfate solution and extracted with CH₂Cl₂. The organic layerwas washed with brine and dried over anhydrous sodium sulfate. Thesolvent was concentrated under reduced pressure to yield3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (140 mg, crude)which was carried through without further purification. ¹H NMR (400 MHz,CDCl₃) δ 10.13 (s, 1H), 8.64 (s, 1H), 8.41-8.39 (dt, J=7.8 Hz, 1.5 Hz,1H), 8.13-8.11 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H).

1-(4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)methanamine

Sodium triacetoxy borohydride (200 mg, 0.9 mmol) was added to a solutionof 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (140 mg, 0.6mmol) and (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine(170 mg, 0.6 mmol) in dry dichloroethane (20 mL) at 0° C. under nitrogenatmosphere and stirred at room temperature for 8 h. The reaction mixturewas carefully quenched with 10% NaHCO₃ solution and extracted withEtOAc. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica 60-120 mesh, eluent 20-25%EtOAc in petroleum ether) to get1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)methanamine(65 mg, yield 22%): ¹H NMR (400 MHz, CDCl₃) δ 7.98 (m, 2H), 7.89 (d,J=7.6 Hz, 2H), 7.48 (s, 1H), 7.46-7.27 (m, 5H), 3.86-3.81 (m, 4H),3.69-3.64 (m, 2H), 2.91 (s, 2H), 2.36 (m, 2H), 2.03-1.97 (ddd, J=13.7Hz, 9.7 Hz, 4 Hz, 2H). MS (ESI) m/z: Calculated for C₂₆H₂₃F₃N₄O₂S:500.15; found: 501.0 (M−H)⁻.

Example 8 Methyl-5-bromonicotinate

A solution of 5-bromonicotinic acid (10 g, 49.5 mmol) in MeOH (200 mL)was cooled to 0° C. and conc. H₂SO₄ (5 mL) was added dropwise. Thereaction mixture was heated to reflux for 12 h. After completion, thereaction mixture was concentrated under reduced pressure, diluted withwater and the aqueous layer was washed with EtOAc. The resulting mixturewas poured over an aqueous saturated NaHCO₃ solution to adjust the pH7-8, it was then extracted with EtOAc and the organic layer was driedover anhydrous Na₂SO₄. Solvent was evaporated under reduced pressure toget the solid product methyl 5-bromonicotinate as an off-white solid (7g, yield 66%): ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.86 (s, 1H),8.45 (s, 1H), 3.98 (s, 3H)

Methyl 5-cyanonicotinate

CuCN (5.22 g, 58.3 mmol) was added to a solution of methyl5-bromonicotinate (6 g, 27.8 mmol) in dry DMF (150 mL). The solution waspurged with argon and heated to 160° C. for 12 h under argon atmosphere.The reaction mixture was cooled to room temperature and then quenchedwith saturated WWI solution. Further EtOAc was added and the reactionmixture was stirred for 10 min. The reaction mixture was filteredthrough a Celite plug, the organic layer was separated, washed withwater and brine, and dried over anhydrous Na₂SO₄. Solvent was evaporatedunder reduced pressure to get methyl-5-cyano-nicotinate asgreenish-white solid (2.7 g, yield 60%): ¹H NMR (300 MHz, DMSO-d₆) δ9.29-9.27 (m, 2H), 8.77 (s, 1H), 3.91 (s, 3H)

3-Cyanonicotinic acid

LiOH (150 mg, 6.2 mmol) was added to solution of methyl5-cyanonicotinate (1 g, 6.17 mmol) in THF-H₂O (7:3 v/v, 50 mL) at 0° C.The reaction mixture was stirred at room temperature for 1 h. THF wasthen removed under reduced pressure and the reaction mixture was dilutedwith water and washed with EtOAc. The resulting reaction mixture wasacidified with 1.5N HCl to pH 3-4. The mixture was extracted with EtOAcand the organic layer was dried over anhydrous Na₂SO₄. Solvent wasevaporated under reduced pressure to get 3-cyanonicotinic acid as anoff-white solid (0.7 g, yield 78%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.9 (brs, 1H), 9.27 (s, 1H), 9.23 (s, 2H), 8.71 (s, 1H). MS (ESI) m/z:Calculated for C₇H₄N₂O₂: 148.03; found: 147.0 (M−H)⁻.

5-(N′-Hydroxycarbamimidoyl)nicotinic acid

This compound was synthesized from 5-cyanonicotinic acid as described inexample 1 step 4 (330 mg, yield 54%): ¹H NMR (400 MHz, DMSO-d₆) δ 13.54(br s, 1H), 9.98 (s, 1H), 9.16 (m, 2H), 8.49 (s, 1H), 6.11 (br s, 2H).MS (ESI) m/z: Calculated for C₇H₇N₃O₃: 181.05; found: 182.2 (M+H)⁺.

5-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid

This compound was synthesized from 5-(N′-hydroxycarbamimidoyl)nicotinicacid as described in example 1 step 5 (260 mg, yield 63%). ¹H NMR (400MHz, DMSO-d₆) δ 13.93 (br s, 1H), 9.43 (d, J=2.1 Hz, 1H), 9.31 (d, J=2.1Hz, 1H), 8.77 (t, J=2.1 Hz, 1H). MS (ESI) m/z: Calculated forC₉H₄F₃N₃O₃: 259.02; found: 258.0 (M−H)⁻.

Step 6:N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

To a stirred solution of compound5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid (100 mg, 0.4mmol) in dry DMF (5 mL) were added HATU (180 mg, 0.46 mmol) followed byhydrochloride salt of(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (120 mg,0.4 mmol) and NMM (0.12 mL, 1.1 mmol) at 0° C. The reaction mixture wasslowly warmed to room temperature and stirred for further 10 h. Thereaction mixture was diluted with EtOAc. The organic layer was washedwith water and brine solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica 60-120 mesh, eluent 50-60% EtOAc inpetroleum ether) to get pure productN-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide(70 mg, yield 37%): ¹H NMR (400 MHz, CDCl₃) δ 9.43 (d, J=2 Hz, 1H), 9.21(br s, 1H), 8.76 (br s, 1H), 7.87 (d, J=7 Hz, 2H), 7.75 (br s, 1H), 7.53(s, 1H), 7.41-7.32 (m, 3H), 3.99-3.95 (m, 2H), 3.79-3.74 (m, 2H),2.35-2.32 (m, 2H), 2.07-2.03 (m, 2H). MS (ESI) m/z: Calculated forC₂₄H₂₀F₃N₅O₃S: 515.12; found: 516.0 (M+H)⁺.

Example 9 5-((4-Phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one

A solution of 4-phenyl thiophene-2-carboxaldehyde (1 g, 5.3 mmol) andrhodanine (700 mg, 5.3 mmol) in 10 mL of glacial acetic acid was heatedwith anhydrous sodium acetate (1.22 g, 14.8 mmol) for 2 h. The reactionmixture was then poured into cold water. The precipitate was filtered,washed with water and dried under reduced pressure to get5-((4-phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g,yield 87%). MS (ESI) m/z: Calculated for C₁₄H₉NOS₃: 302.98; found: 302.0(M−H)⁻. The crude product was carried through without furtherpurification.

3-(4-Phenylthiophen-2-yl)-2-thioxopropanoic acid

A suspension of product5-((4-phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g,4.6 mmol) in 12 mL of 10% aqueous NaOH was heated to 95° C. for 1 h. Thesolution was cooled to room temperature and diluted with water. Theaqueous phase was washed with EtOAc, and acidified with 10% HCl. Theprecipitate that was formed was filtered, washed with water and driedunder reduced pressure to get the product3-(4-phenylthiophen-2-yl)-2-thioxopropanoic acid (0.9 g, yield 74%). MS(ESI) m/z: Calculated for C₁₃H₁₀O₂S₂: 262.01; found: 261.0 (M−H)⁻. Thecrude product was carried through without further purification

2-(Hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid

3-(4-Phenylthiophen-2-yl)-2-thioxopropanoic acid (0.9 g, 3.4 mmol),hydroxylamine hydrochloride (740 mg, 10.6 mmol), and an ethanolicsolution sodium ethoxide [prepared from 0.4 g of sodium and 30 mL ofabsolute ethanol] was refluxed for 1.5 h. Solvent was removed underreduced pressure and the residue was diluted with water and acidifiedwith 1.5N HCl to adjust the pH of the solution ˜3. The solid product wasextracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄,then removal of the solvent under reduced pressure yielded2-(hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid (0.8 g, yield89%) as an off-white solid. ¹H NMR (400 MHz, MeOD) δ 7.59-7.57 (m, 2H),7.37-7.33 (m, 3H), 7.24-7.23 (m, 2H), 3.31 (s, 2H). MS (ESI) m/z:Calculated for C₁₃H₁₁NO₃S: 262.05; found: 262.0 (M+H)⁺.

2-(4-Phenylthiophen-2-yl)acetonitrile

2-(Hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid (0.8 g, 3.1mmol) was heated in acetic anhydride (5 mL) for 1.5 h. The reactionmixture was cooled to room temperature and treated with water. Theproduct was extracted with EtOAc and the organic layer was washed withH₂O and brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) toafford 2-(4-phenylthiophen-2-yl)acetonitrile (0.45 g, yield 73%) as apale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.53 (m, 2H),7.43-7.39 (m, 2H), 7.37-7.36 (m, 2H), 7.34-7.30 (m, 1H), 3.96 (s, 2H).

4-(4-Phenylthiophen-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from 2-(4-phenylthiophen-2-yl)acetonitrileas described in example 1 step 2 (0.32 g, yield 68%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 7.59-7.57 (dd, J=8.2 Hz, 1.1 Hz, 2H),7.45-7.40 (m, 4H), 7.35-7.31 (m, 1H), 4.11-4.07 (m, 2H), 3.93-3.86 (td,J=12 Hz, 2.4 Hz, 2H), 2.29-2.15 (m, 4H).

(4-(4-Phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-phenylthiophen-2-yl)tetrahydro-2H-pyran-4-carbonitrile as describedin example 1 step 3 (210 mg, yield 65%). ¹H NMR (400 MHz, CDCl₃) δ7.61-7.59 (d, J=7.3 Hz, 2H), 7.43-7.30 (m, 4H), 7.19-7.18 (d, J=1 Hz,1H), 3.86-3.82 (m, 2H), 3.62-3.57 (m, 2H), 2.69 (br s, 2H), 2.11-1.96(m, 2H), 1.81-1.74 (m, 2H). MS (ESI) m/z: Calculated for C₁₆H₁₉NOS:273.12; found: 274.2 (M+H)⁺.

N-((4-(4-Phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (80 mg, yield 20%). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (m,1H), 8.25 (d, J=7.8 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.62-7.58 (m, 3H),7.45 (d, J=1.2 Hz, 1H), 7.40 (t, J=7.7 Hz, 2H), 7.31 (m, 1H), 7.23 (d,J=1.5 Hz, 1H), 6.15 (t, J=6.5 Hz, 1H), 3.96-3.91 (dt, J=11.9 Hz, 4.2 Hz,2H), 3.74 (d, J=6.4 Hz, 2H), 3.71-3.66 (m, 2H), 2.18-2.14 (m, 2H),2.08-2.03 (m, 2H). MS (ESI) m/z: Calculated for C₂₆H₂₂F₃N₃O₃S: 513.13;found: 514.2 (M+H)⁺.

Example 10 1-(4-Phenylthiazol-2-yl)cyclopentanecarbonitrile

This compound was synthesized from 2-(4-phenylthiazol-2-yl)acetonitrileas described in example 1 step 2 using 1,4-dibromobutane (580 mg, yield91%). ¹H NMR (300 MHz, CDCl₃) δ 7.93-7.92 (m, 2H), 7.90-7.33 (m, 4H),2.58-2.49 (m, 4H), 2.06-2.00 (m, 4H). MS (ESI) m/z: Calculated forC₁₅H₁₄N₂S: 254.09; found: 255.2 (M+H)⁺.

(1-(4-Phenylthiazol-2-yl)cyclopentyl)methanamine

This compound was synthesized from1-(4-phenylthiazol-2-yl)cyclopentanecarbonitrile as described in example1 step 3 (250 mg, yield 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.96-7.93 (m,3H), 7.44-7.40 (m, 2H), 7.33-7.29 (m, 1H), 2.85 (s, 2H), 2.06-3.01 (m,2H), 1.94-1.87 (m, 2H), 1.73-1.66 (m, 6H). MS (ESI) m/z: Calculated forC₁₆H₁₈N₂S: 258.12; found: 259.2 (M+H)⁺.

N-((1-(4-Phenylthiazol-2-yl)cyclopentyl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(1-(4-phenylthiazol-2-yl)cyclopentyl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (65 mg, yield 34%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.78(m, 1H), 8.44 (s, 1H), 8.19 (d, J=7.6 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H),7.98 (s, 1H), 7.93 (d, J=7.3 Hz, 2H), 7.71 (t, J=7.9 Hz, 1H), 7.39 (m,2H), 7.30 (m, 1H), 3.69 (d, J=6.2 Hz, 2H), 2.19 (m, 2H), 2.07 (m, 2H),1.76 (m, 2H), 1.64 (m, 2H). MS (ESI) m/z: Calculated for C₂₅H₂₁F₃N₄O₂S:498.13; found: 499.2 (M+H)⁺.

Example 114-(3-Phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from(5-phenyl-2H-[1,2,4]triazol-3-yl)-acetonitrile as described in example 1step 2 (0.22 g, yield 16%). ¹H NMR (300 MHz, CDCl₃) δ 7.96-7.92 (dd,J=6.6 Hz, 3.1 Hz, 2H), 7.54-7.49 (m, 3H), 4.09-4.03 (dt, J=12.1 Hz, 3.7Hz, 2H), 3.95-3.87 (m, 2H), 2.44-2.38 (m, 2H), 2.29-2.25 (m, 2H). MS(ESI) m/z: Calculated for C₁₄H₁₄N₄O: 254.12; found: 255.2 (M+H)⁺.

(4-(3-Phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(3-phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (170 mg, crude). ¹H NMR (300 MHz, DMSO-d₆)δ 8.05-8.02 (dd, J=8.0 Hz, 1.4 Hz, 2H), 7.51-7.40 (m, 3H), 3.76-3.72 (m,2H), 3.42-3.38 (m, 2H), 2.97 (br s, 2H), 2.23-2.18 (d, J=11.8 Hz, 2H),1.76-1.68 (m, 2H). MS (ESI) m/z: Calculated for C₁₄H₁₈N₄O: 258.15;found: 259.2 (M+H)⁺.

N-((4-(3-Phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(3-phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (80 mg, yield 24%). ¹H NMR (400 MHz,CDCl₃) δ 8.56 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H),8.02 (dd, J=7.3 Hz, 1.8 Hz, 2H), 7.89 (br s, 1H), 7.62 (t, J=7.8 Hz,1H), 7.46 (m, 3H), 3.97-3.92 (dt, J=11.9 Hz, 4.5 Hz, 2H), 3.83 (d, J=5.8Hz, 2H), 3.71-3.66 (m, 2H), 2.44-2.42 (d, J=13.6 Hz, 2H), 1.96-1.89(ddd, J=13.4 Hz, 9.2 Hz, 3.5 Hz, 2H). MS (ESI) m/z: Calculated forC₂₄H₂₁F₃N₆O₃: 498.16; found: 499.2 (M+H)⁺.

Example 12 4-(2-Phenylthiazol-4-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from (2-phenyl-thiazol-4-yl)-acetonitrileas described in example 1 step 2 (0.53 g, yield 79%) as a yellow solid.¹H NMR (300 MHz, CDCl₃) δ 7.98-7.94 (dd, J=6.5 Hz, 3.2 Hz, 2H),7.47-7.43 (m, 3H), 7.33 (s, 1H), 4.12-4.08 (ddd, J=12.3 Hz, 3.9 Hz, 1.5Hz, 2H), 3.93-3.85 (td, J=12.3 Hz, 2.1 Hz, 2H), 2.49-2.38 (ddd, J=13.7Hz, 12.3 Hz, 4.5 Hz, 2H), 2.18-2.13 (dd, J=13.6 Hz, 2.0 Hz, 2H). MS(ESI) m/z: Calculated for C₁₅H₁₄N₂OS: 270.08; found: 271.2 (M+H)⁺.

(4-(2-Phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(2-phenylthiazol-4-yl)tetrahydro-2H-pyran-4-carbonitrile as describedin example 1 step 3 (380 mg, yield 72%). ¹H NMR (400 MHz, CDCl₃) δ7.96-7.94 (dd, J=7.5 Hz, 2.0 Hz, 2H), 7.47-7.41 (m, 3H), 6.99 (s, 1H),3.89-3.84 (dt, J=11.7 Hz, 4.0 Hz, 2H), 3.58-3.52 (m, 2H), 2.91 (s, 2H),2.31-2.28 (d, J=13.8 Hz, 2H), 1.87-1.80 (ddd, J=13.9 Hz, 10.2 Hz, 4.3Hz, 2H). MS (ESI) m/z: Calculated for C₁₅H₁₈N₂OS: 274.11; found: 275.2(M+H)⁺.

N-((4-(2-Phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(2-phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (85 mg, yield 45%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.56(t, J=6.2 Hz, 1H), 8.41 (m, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.6Hz, 1H), 7.91-7.89 (m, 2H), 7.69-7.65 (t, J=7.8 Hz, 1H), 7.53 (s, 1H),7.46-7.43 (dd, J=4.8 Hz, 1.9 Hz, 3H), 3.79-3.76 (m, 2H), 3.54-3.52 (d,J=6.2 Hz, 2H), 3.37 (m, 2H), 2.26-2.22 (d, J=13.8 Hz, 2H), 1.89-1.84 (m,2H). MS (ESI) m/z: Calculated for C₂₄H₂₁F₃N₄O₃S: 514.13; found: 515.0(M+H)⁺.

Example 13 2-(4-(4-Methoxyphenyl)thiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-(4-methoxyphenyl)ethanoneand 2-cyanothioacetamide as described in example 1 step 1 (1.5 g, yield75%). ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.9 Hz, 2H), 7.35 (s, 1H),6.98 (d, J=8.9 Hz, 2H), 4.17 (s, 2H), 3.86 (s, 3H). MS (ESI) m/z:Calculated for C₁₂H₁₀N₂OS: 230.05; found: 231.2 (M+H)⁺.

4-(4-(4-Methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(4-methoxyphenyl)thiazol-2-yl)acetonitrile as described in example1 step 2 (1.6 g, yield 82%). ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.8Hz, 2H), 7.36 (s, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.11-4.07 (m, 2H),3.96-3.87 (dd, J=11.3 Hz, 2.5 Hz, 2H), 3.86 (s, 3H), 2.41-2.31 (m, 4H).MS (ESI) m/z: Calculated for C₁₆H₁₆N₂O₂S: 300.09; found: 301.2 (M+H)⁺.

(4-(4-(4-Methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(4-methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (200 mg, yield 40%). ¹H NMR (300 MHz,CDCl₃) δ 7.86 (d, J=8.8 Hz, 2H), 7.33 (s, 1H), 6.97 (d, J=8.8 Hz, 2H),3.93-3.88 (m, 5H), 3.68-3.59 (m, 2H), 2.97 (s, 2H), 2.33 (m, 2H),1.94-1.86 (m, 2H). MS (ESI) m/z: Calculated for C₁₆H₂₀H₂O₂S: 304.12;found: 305.2 (M+H)⁺.

N-((4-(4-(4-Methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-(4-methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (80 mg, yield 38%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.78 (t, J=6.3 Hz, 1H), 8.43 (s, 1H), 8.20 (d, J=7.9 Hz, 1H),8.07 (d, J=7.9 Hz, 1H), 7.91 (s, 1H), 7.86 (d, J=8.9 Hz, 2H), 7.71 (t,J=7.8 Hz, 1H), 6.95 (d, J=8.5 Hz, 2H), 3.86 (m, 2H), 3.77 (s, 3H), 3.58(d, J=6.4 Hz, 2H), 3.43 (t, J=10.5 Hz, 2H), 3.33 (s, 2H), 2.25 (d, J=14Hz, 2H), 2.02 (m, 2H). MS (ESI) m/z: Calculated for C₂₆H₂₃F₃N₄O₄S:544.14; found: 545.2 (M+H)⁺.

Example 14 2-(4-(4-Chlorophenyl)thiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-(4-chlorophenyl)ethanoneand 2-cyanothioacetamide as described in example 1 step 1 (1.51 g, yield75%). ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=8.8 Hz, 2H), 7.49 (s, 1H),7.43 (d, J=8.8 Hz, 2H), 4.18 (s, 2H). MS (ESI) m/z: Calculated forC₁₁H₇ClN₂S: 234.00; found: 235.0 (M+H)⁺.

4-(4-(4-Chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)acetonitrile as described in example 1step 2 (1.15 g, yield 86%). ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=8.6 Hz,2H), 7.50 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 4.14-4.07 (dt, J=12.3 Hz, 3.4Hz, 2H), 3.95-3.86 (m, 2H), 2.45-2.30 (m, 4H). MS (ESI) m/z: Calculatedfor C₁₅H₁₃ClN₂OS: 304.04; found: 305.0 (M+H)⁺.

(4-(4-(4-Chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (250 mg, yield 50%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.14 (s, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H),3.79-3.75 (m, 2H), 3.47-3.42 (m, 2H), 2.81 (s, 2H), 2.13 (d, J=13.7 Hz,2H), 1.91-1.83 (m, 2H). MS (ESI) m/z: Calculated for C₁₅H₁₇ClN₂OS:308.08; found: 309.2 (M+H)⁺.

N-((4-(4-(4-Chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized(4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (75 mg, yield 42%). ¹H NMR (400 MHz,CDCl₃) δ 8.47 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.99 (d, J=9 Hz, 1H),7.83 (m, 2H), 7.59 (t, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (t, J=5.4 Hz,1H), 7.35 (d, J=8.5 Hz, 2H), 3.99-3.94 (m, 2H), 3.58 (d, J=5.8 Hz, 2H),3.77-3.71 (m, 2H), 2.35-2.29 (m, 2H), 2.08-2.05 (m, 2H). MS (ESI) m/z:Calculated for C₂₆H₂₀ClF₃N₄O₃S: 548.09; found: 549.0 (M+H)⁺.

Example 15 2-Methyl-2-(4-phenylthiazol-2-yl)propanenitrile

This compound was synthesized from 2-(4-phenylthiazol-2-yl)acetonitrileas described in example 1 step 2 using iodomethane (250 mg, crude). ¹HNMR (300 MHz, CDCl₃) δ 7.94-7.91 (m, 2H), 7.47 (s, 1H), 7.46-7.36 (m,3H), 1.93 (s, 6H).

2-Methyl-2-(4-phenylthiazol-2-yl)propan-1-amine

This compound was synthesized from2-methyl-2-(4-phenylthiazol-2-yl)propanenitrile as described in example1 step 3 (100 mg, yield 45%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.95-7.93 (m,3H), 7.44-7.40 (t, J=7.3 Hz, 2H), 7.33-7.31 (m, 1H), 2.81 (s, 2H), 1.35(s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₆N₂S: 232.10; found: 233.2(M+H)⁺.

N-(2-Methyl-2-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(4-phenylthiazol-2-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (75 mg, yield 38%). ¹H NMR (400 MHz, MeOD) δ 8.52 (t,J=1.8 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.92-7.90(m, 2H), 7.69 (s, 1H), 7.67-7.63 (t, J=7.8 Hz, 1H), 7.36-7.29 (m, 2H),7.28-7.26 (m, 1H), 3.79 (d, J=6.3 Hz, 2H), 1.58 (s, 6H). MS (ESI) m/z:Calculated for C₂₃H₁₉F₃N₄O₂S: 472.12; found: 473.0 (M+H)⁺.

Example 16 1-Methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile

This compound was synthesized from 2-(4-phenylthiazol-2-yl)acetonitrileas described in example 1 step 2 using2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride and heatingthe reaction mixture at 60° C. overnight (200 mg, 40% yield). MS (ESI)m/z: Calculated for C₁₆H₁₇N₃S: 283.11; found: 284.1 (M+H)⁺.

Step 1b: Alternate synthesis of1-methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile

Sodium amide (878 mg, 22.4 mmol) was suspended in toluene (15 mL) andcooled to 0° C. To this suspension was added dropwise a solution of(4-phenyl-thiazol-2-yl)-acetonitrile (1.5 g, 7.4 mmol) in toluene (10mL) while maintaining the temperature at 0° C. The reaction mixture wasstirred for 20 min. Separately the bis-(2-chloroethyl)methylaminehydrochloride (1.45 g, 7.4 mmol) was taken in water (8 mL), cooled to 0°C., and basified with aqueous ammonia solution (adjusted to pH of thesolution to ˜8). The oily layer was separated out from the aqueous layerand the organic product was extracted with toluene. The toluene layerwas dried over sodium hydroxide pellets. The dry toluene solution ofbis-(2-chloroethyl)methylamine was added to the reaction mixture at 0°C. The reaction mixture was allowed to warm up to room temperature andfurther heated to 110° C. for 3 h. The reaction mixture was then cooledto room temperature, diluted with EtOAc, and extracted with EtOAc. Thecombined extracts were washed with water and brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica gel 60-120 mesh,eluent 5% MeOH in CH₂Cl₂) to afford1-methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile (350 mg,yield 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.99-7.97 (m, 2H),7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H), 2.92-2.90 (m, 2H), 2.40-2.37 (m,2H), 2.31-2.16 (m, 7H). MS (ESI) m/z: Calculated for C₁₆H₁₇N₃S: 283.11;found: 284.2 (M+H)⁺.

(1-Methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methanamine

This compound was synthesized from1-methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile as describedin example 1 step 3 (200 mg, crude). MS (ESI) m/z: Calculated forC₁₆H₂₁N₃S: 287.15; found: 288.1 (M+H)⁺.

N-((1-Methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(1-methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (9 mg, 23% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.51 (s,1H), 8.21 (d, J=7.5 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.86 (d, J=6.3 Hz,1H), 7.78 (m, 1H), 7.54 (t, J=6.2 Hz, 2H), 7.48 (s, 1H), 7.34-7.25 (m,2H), 3.86 (s, 2H), 2.69 (m, 2H), 2.57 (m, 4H), 2.34 (s, 3H), 2.13 (m,2H). MS (ESI) m/z: Calculated for C₂₆H₂₄F₃N₅O₂S: 527.16; found: 528.1(M+H)⁺.

Example 17 2-(4-(4-Fluorophenyl)thiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-(4-fluorophenyl)ethanoneand 2-cyanothioacetamide as described in example 1 step 1 (3.2 g, yield72%). MS (ESI) m/z: Calculated for C₁₁H₇FN₂S: 218.03; found: 219.0(M+H)⁺.

4-(4-(4-Fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile as described in example 1step 2 (3.0 g, yield 66%). MS (ESI) m/z: Calculated for C₁₅H₁₃FN₂OS:288.07; found: 289.0 (M+H)⁺.

(4-(4-(4-Fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (600 mg, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₅H₁₇FN₂OS:292.10; found: 293.1 (M+H)⁺.

N-(4-(4-(4-Fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (11 mg, 27% yield): 1H NMR (300 MHz,CDCl3) δ 8.45 (s, 1H), 8.23 (d, J=6.4 Hz, 1H), 7.98 (d, J=6.4 Hz, 1H),7.85 (t, J=5.1 Hz, 2H), 7.55 (t, J=7.7 Hz, 1H), 7.25 (s, 1H), 7.04 (t,J=7.7 Hz, 2H) 3.94 (m, 2H), 3.87 (m, 2H), 3.21 (m, 2H), 2.28 (m, 2H),2.04 (m, 2H). MS (ESI) m/z: Calculated for C₂₅H₂₀F₄N₄O₃S: 532.12; found:533.2 (M+H)⁺.

Example 18 2-(5-Methyl-4-phenylthiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-phenylpropan-1-one and2-cyanothioacetamide as described in example 1 step 1 (1.7 g, 56% yield%). MS (ESI) m/z: Calculated for C₁₂H₁₀N₂S: 214.06; found: 215.0 (M+H)⁺.

4-(5-Methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(5-methyl-4-phenylthiazol-2-yl)acetonitrile as described in example 1step 2 (3.0 g, yield 66%). MS (ESI) m/z: Calculated for C₁₆H₁₆N₂OS:284.10; found: 258.1 (M+H)⁺.

(4-(5-Methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (600 mg, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₆H₂₀N₂OS:288.13; found: 289.1 (M+H)⁺.

N-((4-(5-Methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (55 mg, 89% yield): 1H NMR (300 MHz,CDCl3) δ 8.48 (t, J=1.1 Hz, 1H), 8.23 (dt, J=6.2 Hz, 1.1, 1H), 7.98 (dt,J=7.9 Hz, 1.1 Hz, 1H), 7.74 (bs, 1H), 7.64 (m, 2H), 7.49 (t, J=7.7 Hz,1H), 7.39-7.29 (m, 2H), 3.92 (m, 2H), 3.85 (d, J=5.7 Hz, 2H), 3.74 (m,2H), 2.59 (s, 3H), 2.24 (m, 2H), 1.95 (m, 2H). MS (ESI) m/z: Calculatedfor C₂₆H₂₃F₃N₄O₃S: 528.14; found: 529.1 (M+H)⁺.

Example 19 2-(4-Cyclohexylthiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-cyclohexylethanone and2-cyanothioacetamide as described in example 1 step 1 (0.4 g, yield80%). ¹H NMR (300 MHz, CDCl₃) δ 6.88 (s, 1H), 4.11 (s, 2H), 2.74 (m,1H), 2.06-2.04 (m, 2H), 1.84-1.72 (m, 4H), 1.44-1.31 (m, 4H). MS (ESI)m/z: Calculated for C₁₁H₁₄N₂S: 206.09; found: 207.2 (M+H)⁺.

4-(4-Cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-cyclohexylthiazol-2-yl)acetonitrile as described in example 1 step2 (0.3 g, yield 60%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 6.87(s, 1H), 4.07-4.03 (dt, J=12.2 Hz, 3.3 Hz, 2H), 3.90-3.83 (m, 2H), 2.77(m, 1H), 2.35-2.25 (m, 4H), 2.08-2.06 (d, J=6.0 Hz, 2H), 1.83-1.72 (m,4H), 1.43-1.33 (m, 4H). MS (ESI) m/z: Calculated for C₁₅H₂₀N₂OS: 276.13;found: 277.2 (M+H)⁺.

(4-(4-Cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (120 mg, yield 40%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.14 (s, 1H), 3.75-3.69 (m, 2H), 3.39-3.34 (m, 4H), 2.69 (m,1H), 2.03 (m, 4H), 1.83-1.67 (m, 6H), 1.43 (m, 4H). MS (ESI) m/z:Calculated for C₁₅H₂₄N₂OS: 280.16; found: 281.2 (M+H)⁺.

N-((4-(4-Cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (70 mg, yield 32%). ¹H NMR (400 MHz, MeOD) δ 8.50 (t,J=1.5 Hz, 1H), 8.29 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.98 (m, 1H), 7.67 (t,J=7.8 Hz, 1H), 7.05 (s, 1H), 3.90-3.86 (dt, J=11.8 Hz, 3.9 Hz, 2H), 3.65(s, 2H), 3.55-3.49 (m, 2H), 2.69 (m, 1H), 2.35 (d, J=13.8 Hz, 2H),2.04-1.96 (m, 4H), 1.76-1.73 (m, 2H), 1.39 (m, 6H). MS (ESI) m/z:Calculated for C₂₅H₂₇F₃N₄O₃S: 520.18; found: 521.2 (M+H)⁺.

Example 20 2-(4-(Pyridin-2-yl)thiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-(pyridin-2-yl)ethanone and2-cyanothioacetamide as described in example 1 step 1 (0.37 g, yield73%): ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=5.5 Hz, 1H), 8.15 (m, 2H),7.84 (t, J=8.4 Hz, 1H), 7.30 (m, 1H), 4.21 (s, 2H). MS (ESI) m/z:Calculated for C₁₀H₇N₃S: 201.04; found: 202.2 (M+H)⁺.

4-(4-(Pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(pyridin-2-yl)thiazol-2-yl)acetonitrile as described in example 1step 2 (0.37 g, yield 74%): ¹H NMR (300 MHz, CDCl₃) δ 8.64 (d, J=3.9 Hz,1H), 8.18 (m, 2H), 7.83 (td, J=7.8 Hz, 1.8 Hz, 1H), 7.29 (m, 1H),4.14-4.08 (m, 2H), 3.96-3.87 (m, 2H), 2.46-2.32 (m, 4H). MS (ESI) m/z:Calculated for C₁₄H₁₃N₃OS: 271.08; found: 272.2 (M+H)⁺.

(4-(4-(Pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (150 mg, crude), and it was carriedthrough without any further purification. MS (ESI) m/z: Calculated forC₁₄H₁₇N₃OS: 275.11; found: 276.2 (M+H)⁺.

N-((4-(4-(Pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (35 mg, yield 13%). ¹H NMR (400 MHz, MeOD)δ 8.54 (d, J=5.5 Hz, 1H), 8.44 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.17 (s,1H), 8.11 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.79 (td, J=7.7 Hz,1.6 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.32 (m, 1H), 3.97-3.93 (dt, J=11.8Hz, 3.8 Hz, 2H), 3.75 (m, 2H), 3.62-3.56 (m, 2H), 2.47-2.44 (m, 2H),2.12-2.08 (ddd, J=14.1 Hz, 10.5 Hz, 4.3 Hz, 2H). MS (ESI) m/z:Calculated for C₂₄H₂₀F₃N₅O₃S: 515.12; found: 516.0 (M+H)⁺.

Example 21 2-(4-(Pyridin-4-yl)thiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-(pyridin-4-yl)ethanone and2-cyanothioacetamide as described in example 1 step 1 (0.23 g, yield46%): ¹H NMR (300 MHz, MeOD) δ 8.59 (m, 2H), 8.24 (s, 1H), 7.98 (m, 2H),4.44 (s, 2H). MS (ESI) m/z: Calculated for C₁₀H₇N₃OS: 201.01; found:202.2 (M+H)⁺.

4-(4-(Pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(pyridin-4-yl)thiazol-2-yl)acetonitrile as described in example 1step 2 (0.18 g, yield 58%): ¹H NMR (300 MHz, MeOD) δ 8.60 (m, 2H), 8.29(s, 1H), 7.99 (m, 2H), 4.10-4.04 (dt, J=12.2 Hz, 3.1 Hz, 2H), 3.88-3.79(m, 2H), 2.37-2.33 (m, 4H). MS (ESI) m/z: Calculated for C₁₄H₁₃N₃OS:271.08; found: 272.2 (M+H)⁺.

(4-(4-(Pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (90 mg, crude), and it was carried throughwithout any further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (m,2H), 8.42 (s, 1H), 7.90 (m, 2H), 3.79-3.74 (m, 2H), 3.51-3.42 (m, 2H),2.79 (s, 2H), 2.14-2.10 (m, 2H), 1.89-1.82 (m, 2H). MS (ESI) m/z:Calculated for C₁₄H₁₇N₃OS: 275.11; found: 276.2 (M+H)⁺.

N-((4-(4-(Pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (60 mg, yield 38%): ¹H NMR (400 MHz,DMSO-d₆) δ 8.82 (t, J=6.3 Hz, 1H), 8.57 (d, J=5.8 Hz, 2H), 8.45 (s, 1H),8.40 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.87 (d,J=5.8 Hz, 2H), 7.70 (t, J=7.8 Hz, 1H), 3.87-3.84 (dt, J=12.1 Hz, 3.4 Hz,2H), 3.59-3.58 (d, J=6.1 Hz, 2H), 3.42 (m, 2H), 2.28-2.24 (d, J=13.4 Hz,2H), 2.04-1.96 (m, 2H). MS (ESI) m/z: Calculated for C₂₄H₂₀F₃N₆O₃S:515.12; found: 516.0 (M+H)⁺.

Example 22 Methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate

Hydroxylamine hydrochloride (420 mg, 6.1 mmol) and pyridine (0.5 mL)were added to a solution of methyl 5-formylthiophene-2-carboxylate (690mg, 4.1 mmol) in EtOH (25 mL). The reaction mixture was refluxed for 3h, cooled to room temperature and concentrated under reduced pressure.The residue was dissolved in diethyl ether, the organic layer was washedwith water and brine, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to get product methyl5-((hydroxyimino)methyl)thiophene-2-carboxylate (440 mg, yield 60%),which was carried through without any further purification. ¹H NMR (400MHz, DMSO-d₆) δ 12.5 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=4.1 Hz, 1H), 7.51(d, J=4.1 Hz, 1H), 3.82 (s, 3H). MS (ESI) m/z: Calculated for C₇H₇NO₃S:185.01; found: 186.0 (M+H)⁺.

Methyl 5-cyanothiophene-2-carboxylate

A solution of methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate(440 mg, 2.4 mmol) in acetic anhydride (10 mL) was refluxed for 16 h.After completion, the reaction mixture was cooled to room temperature,concentrated under reduced pressure and the residue was dissolved indiethyl ether. The organic layer was washed with 10% aqueous NaOHsolution, water and brine, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to yield methyl5-cyanothiophene-2-carboxylate (5-cyano-thiophene-2-carboxylic acidmethyl ester) (400 mg, yield 90%) which was carried through without anyfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (d, J=4.2 Hz,1H), 7.60 (d, J=4.1 Hz, 1H), 3.95 (s, 3H).

Methyl and ethyl 5-(N′-hydroxycarbamimidoyl)thiophene-2-carboxylate

This mixture of compounds was synthesized from methyl5-cyanothiophene-2-carboxylate as described in example 1 step 4 and itwas isolated as a mixture of methyl and ethyl esters (2:3 ratio), and itwas carried through without any further purification. MS (ESI) m/z:Calculated for C₇H₈N₂O₃S: 200.03; found: 201.2 (M+H)⁺. (methyl ester);Calculated for C₈H₁₀N₂O₃S: 214.04; found: 215.0 (M+H)⁺. (ethyl ester)

Methyl and ethyl5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylate

This mixture of compounds was synthesized from a mixture of methyl andethyl 5-(N′-hydroxycarbamimidoyl)thiophene-2-carboxylate as described inexample 1 step 5 and it was isolated as a mixture of methyl and ethylesters (2:3 ratio), and it was carried through without any furtherpurification. MS (ESI) m/z: Calculated for C₉H₅F₃N₂O₃S: 278.00; found:278.0 (M)⁻. (methyl ester); Calculated for C₁₀H₇F₃N₂O₃S: 292.01; found:292.0 (M)⁻. (ethyl ester)

5-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylic acid

LiOH (37 mg) was added to a solution of a mixture of compounds methyland ethyl5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylate (300mg) in THF: H₂O (10 mL, 7:3 v/v) and the mixture was stirred at roomtemperature for 2 days. The reaction mixture was then diluted with waterand the aqueous layer was washed with EtOAc. The aqueous layer wasacidified to pH ˜4, extracted with EtOAc. The combined extracts wereconcentrated under reduced pressure to yield5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylic acid(60 mg), which was carried through without any further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 13.78 (br s, 1H), 8.01-7.94 (m, 1H), 7.84-7.79(dd, J=18.2 Hz, 3.8 Hz, 1H). MS (ESI) m/z: Calculated for C₈H₃F₃N₂O₃S:263.98; found: 263.0 (M−H)⁻.

N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxamide

This compound was synthesized from(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylic acidas described in example 8 step 6 (25 mg, yield 22%): ¹H NMR (400 MHz,CDCl₃) δ 7.96 (d, J=7.3 Hz, 2H), 7.78 (m, J=4.0 Hz, 1H), 7.62 (br s,1H), 7.53-7.48 (m, 4H), 7.42-7.38 (m, 1H), 3.97-3.91 (m, 2H), 3.86 (d,J=5.5 Hz, 2H), 3.78-3.73 (ddd, J=11.6 Hz, 7.5 Hz, 3.5 Hz, 2H), 2.33-2.27(ddd, J=13.6 Hz, 7.0 Hz, 3.5 Hz, 2H), 2.06-1.99 (ddd, J=13.8 Hz, 7.3 Hz,3.3 Hz, 2H). MS (ESI) m/z: Calculated for C₂₃H₁₉F₃N₄O₃S₂: 520.09; found:521.0 (M+H)⁺.

Example 23 2-(4-(Thiophen-2-yl)thiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-(thiophen-2-yl)ethanone and2-cyanothioacetamide as described in example 1 step 1 (0.25 g, yield49%): ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J=3.4 Hz, 1H), 7.36 (s, 1H),7.33 (d, J=5.1 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 4.17 (s, 2H). MS (ESI)m/z: Calculated for C₉H₆N₂S₂: 206.00; found: 207.0 (M+H)⁺.

4-(4-(Thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(thiophen-2-yl)thiazol-2-yl)acetonitrile as described in example 1step 2 (0.2 g, yield 60%): ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.47 (dd,J=3.6 Hz, 1.2 Hz, 1H), 7.36 (s, 1H), 7.32 (dd, J=5.2 Hz, 1.2 Hz, 1H),7.09-7.07 (dd, J=5.0 Hz, 3.5 Hz, 1H), 4.13-4.07 (m, 2H), 3.94-3.85 (td,J=11.8 Hz, 2.5 Hz, 2H), 2.46-2.33 (m, 4H). MS (ESI) m/z: Calculated forC₁₃H₁₂N₂OS₂: 276.04; found: 277.0 (M+H)⁺.

(4-(4-(Thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (80 mg, yield 40%): ¹H NMR (400 MHz,DMSO-d₆) δ 7.88 (s, 1H), 7.54-7.47 (m, 2H), 7.10-7.08 (m, 1H), 3.76-3.72(m, 2H), 3.49-3.39 (m, 2H), 2.79 (s, 2H), 2.08-1.96 (m, 2H), 1.87-1.81(m, 2H). MS (ESI) m/z: Calculated for C₉H₆N₂S₂: 280.07; found: 281.2(M+H)⁺.

N-((4-(4-(Thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (70 mg, yield 46%): ¹H NMR (400 MHz, MeOD)δ 8.47 (t, J=1.5 Hz, 1H), 8.26 (m, 1H), 8.00 (dt, J=7.8 Hz, 1.4 Hz, 1H),7.63-7.61 (m, 2H), 7.46 (dd, J=3.8 Hz, 1.0 Hz, 1H), 7.29 (dd, J=5.0 Hz,1.0 Hz, 1H), 7.01 (dd, J=5.0 Hz, 3.8 Hz, 1H), 3.95-3.92 (dt, J=11.9 Hz,4.0 Hz, 2H), 3.71 (s, 2H), 3.62-3.56 (m, 2H), 2.42-2.38 (d, J=13.8 Hz,2H), 2.08-2.02 (ddd, J=14.3 Hz, 10.4 Hz, 4.4 Hz, 2H), MS (ESI) m/z:Calculated for C₂₃H₁₉F₃N₄O₃S₂: 520.09; found: 521.0 (M+H)⁺.

Example 24 2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropanenitrile

This compound was synthesized from2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile using iodomethane asdescribed in example 1 step 2, and it was used directly without anypurification in the next step. ¹H NMR (CDCl₃) (2H, m), 7.39 (1H, s),7.10 (2H, m), 1.90 (6H, s). MS (ESI) m/z: Calculated for C₁₃H₁₁FN₂S:246.06; found: 247.0 (M+H)⁺.

2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanenitrile as describedin example 1 step 3 (29 mg, 6% yield). ¹H NMR (DMSO-d₆) m), 7.92 (1 h,s), 7.26-7.22 (2H, m), 2.77 (2H, s), 1.33 (6H, s); MS (ESI) m/z:Calculated for C₁₃H₁₆FN₂S: 250.09; found: 251.1 (M+H)⁺.

Step 6:N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine (140 mg, 0.56mmol), 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (144.37mg, 0.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDCI) (214.42 mg, 1.12 mmol), and 1-hydroxybenzotriazole(HOBt) (120.91 mg, 0.89 mmol) were dissolved in dichloromethane (3 mL)at room temperature. Diisopropylethylamine (DIEA) (0.39 mL, 2.24 mmol)was then introduced at room temperature and the reaction mixture wasstirred at room temperature for 2 h. The reaction mixture was dilutedwith dichloromethane (60 mL) and washed with water (1×20 mL) and brine(1×20 mL). The organic layer was then dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give the crudeproduct. The crude product was then purified on Combiflash ISCO (0-30%Ethyl Acetate:Hexanes) to give the desired product (164 mg, 60% yield).¹H NMR (CDCl₃) 8.52 (1H, t), 8.22 (1H, dt), 8.12 (1H, t), 8.03 (1H, dt),7.85-7.81 (2H, m), 7.57 (1H, d), 7.35 (1H, s), 7.05-7.00 (2H, m), 3.80(2H, d, J=4 Hz), 1.55 (6H, s); MS (ESI) m/z: Calculated forC₂₃H₁₈F₄N₄O₂S: 490.11; found: 491.1 (M+H)⁺.

Example 25 2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropanenitrile

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (470 mg, yield 94%): ¹H NMR (400 MHz,CDCl₃) δ 7.86-7.85 (d, J=8.5 Hz, 2H), 7.46 (s, 1H), 7.41-7.39 (d, J=8.5Hz, 2H), 1.92 (s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₁ClN₂S: 262.03;found: 263.0 (M+H)⁺.

2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropanenitrile as describedin example 1 step 3 (120 mg, yield 47%): ¹H NMR (400 MHz, DMSO-d₆) δ8.04 (d, J=1.2 Hz, 1H), 7.98 (dd, J=8.4 Hz, J=1.7 Hz, 2H), 7.51-7.48(dd, J=8.5 Hz, J=1.5 Hz, 2H), 2.81 (s, 2H), 1.37 (s, 6H). MS (ESI) m/z:Calculated for C₁₃H₁₅ClN₂S: 266.06; found: 267.2 (M+H)⁺.

N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (80 mg, yield 35%): ¹H NMR (400 MHz, CDCl₃) δ 8.54 (m,1H), 8.27 (d, J=7.8 Hz, 1H), 8.10-8.04 (m, 2H), 7.82-7.80 (d, J=8.5 Hz,2H), −7.62-7.58 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J=8.5 Hz, 2H),3.82 (d, J=5.8 Hz, 2H), 1.58 (s, 6H). MS (ESI) m/z: Calculated forC₂₃H₁₈ClF₃N₄O₂S: 506.08; found: 507.0 (M+H)⁺.

Example 26 3-Fluoro-5-(N′-hydroxycarbamimidoyl)benzoic acid

This compound was synthesized from 3-cyano-5-fluorobenzoic acid asdescribed in example 1 step 4 (442 mg, yield 37%) and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₈H₇FN₂O₃: 198.04; found: 199.1 (M+H)⁺.

3-Fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

This compound was synthesized from3-fluoro-5-(N′-hydroxycarbamimidoyl)benzoic acid as described in example1 step 5 (351 mg, yield 51%) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₀H₄F₄N₂O₂: 276.02; found:277.1 (M+H)⁺.

3-Fluoro-N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and3-fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (23 mg, yield 32%): ¹H NMR (400 MHz,CDCl₃) δ 8.32 (br s, 1H), 8.23 (br t, J=5 Hz, 1H), 7.94 (br d, J=8 Hz,1H), 7.86-7.75 (m, 3H), 7.06-7.00 (m, 2H), 3.78 (d, J=4 Hz, 2H), 1.55,(s, 6H). MS (ESI) m/z: Calculated for C₂₃H₁₇F₅N₄O₂S: 508.10; found:509.1 (M+H)⁺.

Example 27 Methyl 3,5-dicyanobenzoate

3,5-Dibromomethylbenzoate (1 g, 3.4 mmol) was dissolved in dry DMF (35mL) and copper cyanide (1.2 g, 13.6 mmol) was added. The reactionmixture was heated to 160° C. under argon atmosphere for 26 h, allowedto cool down to room temperature and then quenched with saturatedammonium chloride solution. The reaction mixture was diluted with EtOAcand filtered through a Celite plug. The filtrate was diluted with EtOAcand the organic layer was washed with water and brine. The solvent wasevaporated under reduced pressure to get the crude methyl3,5-dicyanobenzoate (400 mg, crude, confirmed by GC-MS), which wascarried through without further purification.

3,5-Dicyanobenzoic acid

Methyl 3,5-dicyanobenzoate (400 mg, 2.1 mmol) was dissolved in THF-H₂O(7:3 v/v, 30 mL), the solution was cooled to 0° C. and LiOH (51 mg, 2.1mmol) was added. The reaction mixture was allowed to warm up to roomtemperature and stirred for 1 h. THF was removed under reduced pressureand the aqueous layer was washed with EtOAc, acidified to pH ˜2-3 using1.5N HCl, and extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and the solvent was removed under reducedpressure. The crude product was purified by column chromatography(silica 60-120 mesh, eluent 20% MeOH in CHCl₃) to get pure product3,5-dicyanobenzoic acid (100 mg, yield 28%): ¹H NMR (400 MHz, DMSO-d₆) δ8.53 (s, 1H), 8.50 (s, 2H). MS (ESI) m/z: Calculated for C₉H₄N₂O₂:172.03; found: 171.2 (M−H)⁻.

3-Cyano-5-(N′-hydroxycarbamimidoyl)benzoic acid

This compound was synthesized from 3,5-dicyanobenzoic acid as describedin example 1 step 4 (120 g, crude), and it was carried through withoutany further purification. MS (ESI) m/z: Calculated for C₉H₇N₃O₃: 205.05;found: 204.0 (M−H)⁻.

3-Cyano-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

This compound was synthesized from 3-cyano-5-(N′hydroxycarbamimidoyl)benzoic acid as described in example 1 step 5 (45mg, yield 27%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.39 (s, 2H).MS (ESI) m/z: Calculated for C₉H₄N₂O₂: 283.02; found: 282.0 (M−H)⁻.

3-Cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-cyano-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (25 mg, yield 30%): ¹H NMR (400 MHz, MeOD)δ 8.63 (t, J=1.6 Hz, 1H), 8.52 (t, J=1.5 Hz, 1H), 8.25 (t, J=1.6 Hz,1H), 7.87-7.85 (m, 2H), 7.81 (s, 1H), 7.32-7.28 (m, 2H), 7.25-7.21 (m,1H), 3.97-3.92 (m, 2H), 3.71 (s, 2H), 3.62-3.58 (td, J=11.4 Hz, 2.1 Hz,2H), 2.48-2.44 (d, J=13.3 Hz, 2H), 2.11-2.04 (ddd, J=14.3 Hz, 10.5 Hz,4.3 Hz, 2H). MS (ESI) m/z: Calculated for C₂₆H₂₀F₃N₅O₃S: 539.12; found:540.0 (M+H)⁺.

Example 28 3-(N′-Hydroxycarbamimidoyl)-5-methoxybenzoic acid

This compound was synthesized from 3-cyano-5-methoxybenzoic acid asdescribed in example 1 step 4 (500 mg, yield 84%): ¹H NMR (400 MHz,DMSO-d₆) δ 11.27 (br s, 1H), 9.07 (br s, 2H), 7.83 (s, 1H), 7.68 (s,1H), 7.55 (m, 1H), 3.89 (s, 3H). MS (ESI) m/z: Calculated for C₉H₁₀N₂O₄:210.06; found: 211.2 (M+H)⁺.

3-Methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

This compound was synthesized from3-(N′-hydroxycarbamimidoyl)-5-methoxybenzoic acid as described inexample 1 step 5 (170 mg, yield 40%), and it was carried through withoutany further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (t, J=1.3 Hz,1H), 7.74 (dd, J=2.6 Hz, 1.5 Hz, 1H), 7.69 (dd, J=2.6 Hz, 1.5 Hz, 1H),3.91 (s, 3H). MS (ESI) m/z: Calculated for C₁₁H₇F₃N₂O₄: 288.04; found:287.0 (M−H)⁻.

3-Methoxy-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (70 mg, yield 46%): ¹H NMR (400 MHz,CDCl₃) δ 8.75 (t, J=6.3 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.91 (d,J=7.0 Hz, 2H), 7.63 (m, 1H), 7.57 (m, 1H), 7.38-7.35 (m, 2H), 7.30-7.26(m, 1H), 3.85 (s, 3H), 3.83 (m, 2H), 3.56 (d, J=6.5 Hz, 2H), 3.41-3.36(m, 2H), 2.23 (d, J=13.5 Hz, 2H), 2.01-1.94 (m, 2H). MS (ESI) m/z:Calculated for C₂₆H₂₃F₃N₄O₄S: 544.14; found: 545.2 (M+H)⁺.

Example 29 2-(4-(4-Fluorophenyl)thiazol-2-yl)ethanamine

2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile (400 mg, 1.83 mmol) wasdissolved in tetrahydrofuran (10 mL) at room temperature. Boranetetrahydrofuran complex solution (1M in tetrahydrofuran, 9.16 mL, 9.16mmol) was added and the reaction mixture was stirred for 1 h at roomtemperature. The reaction mixture was cooled to 0° C. and quenched withmethanol (5 eq., 0.4 mL). The reaction was allowed to warm to roomtemperature and 2N HCl was added until the reaction mixture wasconfirmed acidic by a pH paper. The reaction mixture was then refluxedat 65° C. for 30 min. The reaction mixture was then allowed to cool toroom temperature and was concentrated under reduced pressure. The solidobtained was triturated with ether (2×20 mL) and dichloromethane (2×20mL). The remaining solid was dissolved in water (50 mL) and basified topH ˜11 with NaOH pellets. The aqueous mixture was then extracted withether (2×100 mL). The organic layer was dried over anhdrous sodiumsulfate and concentrated under reduced pressure to give the crudeproduct, which was used directly without any purification in the nextstep (100 mg, 25% yield). MS (ESI) m/z: Calculated for C₁₁H₁₁FN₂S:222.06; found: 223.1 (M+H)⁺.

N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(4-(4-fluorophenyl)thiazol-2-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 26 step 6 (180 mg, 86% yield). ¹H NMR (CDCl₃) 8.51 (1H, t), 8.22(1H, dt), 8.04 (1H, dt), 7.85-7.81 (2H, m), 7.64 (1H, m), 7.59 (1H, t),7.31 (1H, s), 7.06-7.02 (2H, m), 3.97 (2H, q), 3.35 (2H, t); MS (ESI)m/z: Calculated for C₂₁H₁₄F₄N₄O₂S: 462.08; found: 463.1 (M+H)⁺.

Example 30 2-(4-(4-Bromophenyl)thiazol-2-yl)acetonitrile

This compound was synthesized from 2-bromo-1-(4-bromophenyl)ethanone and2-cyanothioacetamide as described in example 1 step 1 (2.4 g, 48%yield), and it was carried through without further purification. MS(ESI) m/z: Calculated for C₁₁H₇BrN₂S: 277.95; found: 279.0 (M+H)⁺.

4-(4-(4-Bromophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(4-bromophenyl)thiazol-2-yl)acetonitrile as described in example 1step 2 (1.9 g, yield 80%). MS (ESI) m/z: Calculated for C₁₅H₁₃BrN₂OS:347.99; found: 349.0 (M+H)⁺.

(4-(4-(4-Bromophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(4-bromophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (1.7 g), and it was carried throughwithout any further purification. MS (ESI) m/z: Calculated forC₁₅H₁₇BrN₂OS: 352.02; found: 353.0 (M+H)⁺.

4-(2-(4-(Aminomethyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)benzonitrile

(4-(4-(4-Bromophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine(200 mg, 0.56 mmol), zinc cyanide (53 mg, 0.45 mmol), and DMF (2 mL)were placed in microwave tube and degassed.1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (41 mg,0.05 mmol) was added. Reaction was microwaved at 200° C. for 10 minintervals until complete. The reaction was quenched with ammoniumhydroxide/water (1:4) and washed with ethyl acetate. Organic layer wasdried over sodium sulfate. Crude was purified using silicachromatography with an ethyl acetate wash followed by 10% Methanol indichloromethane with 1% triethylamine to yield4-(2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)benzonitrile(20 mg, 10% yield). MS (ESI) m/z: Calculated for C₁₆H₁₇N₃OS: 299.11;found: 300.1 (M+H)⁺.

N-((4-(4-(4-Cyanophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from4-(2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)benzonitrileand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (3 mg, 7% yield). ¹H NMR (300 MHz, CD₃OD)δ 8.40 (d, J=1.8 Hz, 1H), 8.23 (d, J=7.2 Hz, 1H), 8.10-8.07 (m, 2H),7.94 (m, 1H), 7.81 (m, 1H), 7.69-7.53 (m, 3H)) 3.94 (m, 2H), 3.87 (s,2H), 3.55 (m, 2H), 2.45 (m, 2H), 2.08 (m, 2H). MS (ESI) m/z: Calculatedfor C₂₆H₂₀F₃N₅O₃S: 539.12; found: 540.1 (M+H).

Example 314-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile

2-(4-(4-Fluorophenyl)thiazol-2-yl)acetonitrile (325 mg, 1.5 mmol),potassium carbonate (617 mg, 4.47 mmol), and1-chloro-2-(2-chloroethoxy)-2-methylpropane (254 mg, 1.5 mmol) in DMF (5mL) were microwaved at 160° C. for 5 min then 20 min. A second additionof potassium carbonate and 1-chloro-2-(2-chloroethoxy)-2-methylpropanewas made and then the reaction was microwaved again for 30 min twotimes. The reaction was diluted with ethyl acetate and washed withwater. The organic layer was dried over sodium sulfate and purified onsilica using a gradient of 0-30% ethyl acetate/hexanes to afford4-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile(228 mg, 48% yield). MS (ESI) m/z: Calculated for C₁₇H₁₇FN₂OS: 316.10;found: 317.1 (M+H)⁺.

(4-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrileas described in example 1 step 3 (100 mg), and it was carried throughwithout any further purification. MS (ESI) m/z: Calculated forC₁₇H₂₁FN₂OS: 320.14; found: 321.1 (M+H)⁺.

N-((4-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (7 mg, yield 17%): ¹H NMR (500 MHz, CD₃OD)δ 8.41 (t, J=1 Hz, 1H), 8.23 (d, J=4 Hz, 1H), 7.96-7.90 (m, 3H), 7.76(s, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.69-7.04 (t, J=8.8 Hz, 2H), 3.88 (m,2H), 3.60 (s, 2H), 2.52 (m, 2H), 1.95 (m, 2H), 1.29 (s, 3H), 0.81 (s,3H). MS (ESI) m/z: Calculated for C₂₇H₂₄F₄N₄O₃S: 560.15; found: 561.1(M+H)⁺.

Example 32 3-Cyanobenzene-1-sulfonyl chloride

3-Aminobenzonitrile (2.5 g, 21 mmol) was dissolved in conc. HCl (20 mL)and water (20 mL), cooled to 0° C. and a solution of sodium nitrite (1.5g, 22 mmol) in water (5 mL) was added dropwise. The reaction mixture wasstirred for 10 min to complete the diazonium salt formation. In aseparate flask was added copper(I) chloride (0.2 g) over a saturatedsolution of sulfur dioxide in AcOH (25 mL) and stirred at 0° C. for 10min. The resulting solution was added dropwise to the diazonium salt andstirred at 0° C. for 1 h. The reaction mixture poured into ice water andthe product was extracted with tert-butylmethylether. The combinedorganic layer was washed with water and brine. The crude product waspurified by column chromatography (silica gel 60-120 mesh using 5% EtOAcin petroleum ether) to get the pure 3-cyanobenzene-1-sulfonyl chloride(1.9 g, yield 45%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.35(t, J=1.5 Hz, 1H), 8.31-8.27 (m, 1H), 8.06-8.02 (m, 1H), 7.82 (t, J=7.9Hz, 1H).

3-Cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide

Et₃N (0.15 mL, 1.43 mmol) was added dropwise to an ice cold solution of(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (130 mg,0.48 mmol) in dry CH₂Cl₂ (3 mL). The resulting reaction mixture wasstirred at 0° C. for 5 min, then a solution of 3-cyanobenzene-1-sulfonylchloride (105 mg, 0.52 mmol) in dry CH₂Cl₂ (2 mL) was added dropwise.The reaction mixture was further stirred at room temperature for 1 h.The reaction mixture was diluted with CH₂Cl₂ and the organic layer waswashed with H₂O and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleumether) to afford compound3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide(0.13 g, yield 61%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ8.03-7.98 (m, 2H), 7.85-7.76 (m, 3H), 7.59-7.54 (m, 1H), 7.50-7.38 (m,4H), 3.87-3.79 (m, 2H), 3.74-3.66 (m, 2H), 3.36 (s, 2H), 2.27-2.19 (ddd,J=13.5 Hz, 6.7 Hz, 3.5 Hz, 2H), 2.01-1.93 (ddd, J=13.8 Hz, 7.5 Hz, 3.7Hz, 2H). MS (ESI) m/z: Calculated for C₂₂H₂₁N₃O₃S₂: 439.10; found: 440.0(M+H)⁺.

N′-Hydroxy-3-(N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)benzimidamide

This compound was synthesized from3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamideas described in example 1 step 4 (125 mg, yield 89%) and it was carriedthrough without further purification, ¹H NMR (400 MHz, DMSO-d₆) δ 9.83(s, 1H), 8.08 (m, 2H), 7.95 (d, J=7.0 Hz, 2H), 7.86 (d, J=7.9 Hz, 1H),7.79 (t, J=6.7 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.55 (m, 1H), 7.44 (m,2H), 7.34 (m, 1H), 5.96 (s, 2H), 3.78 (m, 2H), 3.41 (t, J=10.2 Hz, 2H),3.01 (d, J=6.7 Hz, 2H), 2.15-2.12 (m, 2H), 1.94-1.87 (m, 2H). MS (ESI)m/z: Calculated for C₂₂H₂₄N₄O₂S₂: 472.12; found: 473.2 (M+H)⁺.

N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzenesulfonamide

This compound was synthesized fromN′-hydroxy-3-(N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)benzimidamideas described in example 1 step 5 (80 mg, yield 57%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.32 (s, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.05 (t, J=6.9 Hz, 1H),7.999 (m, 2H), 7.89 (d, J=7.3 Hz, 2H), 7.76 (t, J=7.8 Hz, 1H), 7.40 (m,2H), 7.30 (m, 1H), 3.79-3.76 (m, 2H), 3.39 (t, J=10.8 Hz, 2H), 3.11 (d,J=6.7 Hz, 2H), 2.16-2.13 (m, 2H), 1.93-1.86 (m, 2H). MS (ESI) m/z:Calculated for C₂₄H₂₁F₃N₄O₂S₂: 550.10; found: 551.0 (M+H)⁺.

Example 33 3-Bromo-5-(methoxycarbonyl)benzoic acid

Dimethyl-5-bromoisophthalate (3 g, 11.0 mmol) was dissolved inacetone-H₂O (2:1 v/v, 60 mL) and NaOH (0.40 g, 11.0 mmol) was added. Thereaction mixture was allowed to stir for 4 h. Acetone was removed underreduced pressure and the aqueous layer was washed with EtOAc, acidifiedto pH ˜2-3 using 1.5N HCl, and extracted with EtOAc. The organic layerwas dried over anhydrous sodium sulfate and the solvent was removedunder reduced pressure to yield 3-bromo-5-(methoxycarbonyl)benzoic acid(2.55 g, yield 89%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.75 (br s, 1H), 8.40(d, J=1.0 Hz, 1H), 8.26 (d, J=1.4 Hz, 1H), 8.23 (d, J=1.0 Hz, 1H), 3.89(s, 3H). MS (ESI) m/z: Calculated for C₉H₇BrO₄: 257.95; found: 258.0(M+H)⁺.

Methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate

N,O-Dimethylhydroxylamine hydrochloride (1.15 g, 11.8 mmol) wasdissolved in CH₂Cl₂ (50 mL) and Et₃N (4.8 mL, 34.4 mmol) was added. Thesolution was stirred for 30 min. The resultant solution was cooled to 0°C. and compound 3-bromo-5-(methoxycarbonyl)benzoic acid (2.55 g, 9.84mmol) was added followed by EDC.HCl (3.77 g, 19.6 mmol) and HOBt (0.26g, 1.96 mmol). The reaction mixture was allowed to come to roomtemperature and stirred for another 4 h. After completion, the reactionmixture was diluted with CH₂Cl₂. The organic layer was washed with waterand brine solution and dried over anhydrous sodium sulfate. Solvent wasremoved under reduced pressure and the crude product was purified bycolumn chromatography (silica 60-120 mesh, eluent 20% EtOAc in petroleumether) to get methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate (2.3g, yield 77%) as colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (m,1H), 8.27 (t, J=1.8 Hz, 1H), 8.02 (t, J=1.6 Hz, 1H), 3.95 (s, 3H), 3.57(s, 3H), 3.39 (s, 3H). MS (ESI) m/z: Calculated for C₁₁H₁₂BrNO₄: 300.99;found: 302.0 (M+H)⁺.

Methyl 3-acetyl-5-bromobenzoate

The compound methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate (2.3 g,7.6 mmol) was dissolved in dry THF (50 mL), solution was cooled to 0° C.and methylmagnesium chloride (3M in THF, 2.5 mL, 7.6 mmol)) was addeddropwise. The reaction mixture was slowly allowed to come to roomtemperature and stirred further for 6 h. The reaction mixture was cooledto 0° C. and quenched with saturated NH₄Cl solution. The product wasextracted with EtOAc. The organic layer was washed with water and brineand dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure. The crude product was purified by columnchromatography (silica 60-120 mesh, eluent 5% EtOAc in petroleum ether)to get methyl 3-acetyl-5-bromobenzoate (0.95 g, yield 49%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (t, J=1.3 Hz, 1H), 8.37 (t, J=1.7Hz, 1H), 8.28 (t, J=1.6 Hz, 1H), 3.97 (s, 3H), 2.65 (s, 3H).

3-Bromo-5-ethylbenzoic acid

The compound methyl 3-acetyl-5-bromobenzoate (1.2 g, 4.8 mmol) wasdissolved in ethylene glycol (10 mL) and KOH (0.41 g, 7.3 mmol) followedby hydrazine hydrate (0.44 mL, 7.3 mmol) were added. The reactionmixture was heated to 200° C. for 1 h. The reaction mixture was cooledto room temperature and diluted with water. The pH of the aqueous layerwas adjusted to 2-3 using 1.5N HCl. The product was extracted withEtOAc. The organic layer was washed with water and brine and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure. The crude product was purified by column chromatography(silica 60-120 mesh, eluent 50% EtOAc in petroleum ether) to yield3-bromo-5-ethylbenzoic acid (0.95 g, yield 89%) as a yellow solid. ¹HNMR (300 MHz, CDCl₃) δ 8.07 (m, 1H), 7.88 (m, 1H), 7.59 (m, 1H), 2.73(q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H). MS (ESI) m/z: Calculated forC₉H₉BrO₂: 227.98; found: 229.0 (M+H)⁺.

Methyl 3-bromo-5-ethylbenzoate

The compound 3-bromo-5-ethylbenzoic acid (0.95 g, 4.14 mmol) wasdissolved in MeOH (50 mL), reaction mixture was cooled to 0° C. andSOCl₂ (0.5 mL) was added. The reaction mixture was allowed to stir atroom temperature for 10 h. The reaction mixture was concentrated underreduced pressure and diluted with CH₂Cl₂. The organic layer was washedwith 10% NaHCO₃ solution, water and brine. The organic phase was driedover anhydrous sodium sulfate and solvent was removed under reducedpressure. Methyl 3-bromo-5-ethylbenzoate (0.92 g, yield 92%) wasisolated as colorless liquid and carried through without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 7.99 (t, J=1.6 Hz, 1H), 7.81 (d,J=1.4 Hz, 1H), 7.54 (t, J=1.6 Hz, 1H), 3.92 (s, 3H), 2.69 (q, J=7.6 Hz,2H), 1.26 (t, J=7.6 Hz, 3H).

Methyl 3-cyano-5-ethylbenzoate

The product methyl 3-bromo-5-ethylbenzoate (0.9 g, 3.7 mmol) wasdissolved in dry DMF (50 mL) and copper cyanide (0.84 g, 9.43 mmol) wasadded. The reaction mixture was heated to 150° C. under argon atmospherefor 12 h (monitored by TLC; petroleum ether/EtOAc 9:1). The reactionmixture was allowed to come to room temperature and then quenched withsaturated ammonium chloride solution. The reaction mixture was dilutedwith EtOAc and filtered through a Celite bed. The filtrate was dilutedwith EtOAc and the organic layer was washed with water and brine. Thesolvent was evaporated under reduced pressure. The crude product waspurified by column chromatography (silica 60-120 mesh, eluent 5% EtOAcin petroleum ether) to get methyl 3-cyano-5-ethylbenzoate (0.27 g, yield39%) as colorless liquid, which was carried through without furtherpurification.

3-Cyano-5-ethylbenzoic acid

The compound methyl 3-cyano-5-ethylbenzoate (270 mg, 1.42 mmol) wasdissolved in THF-H₂O (7:3 v/v, 10 mL), solution was cooled to 0° C. andLiOH (59 mg, 1.42 mmol) was added. The reaction mixture was allowed tocome to room temperature and stirred for 3 h (monitored by TLC;petroleum ether/EtOAc 1:1). Solvent THF was removed under reducedpressure and the aqueous layer was washed with EtOAc to remove thenon-polar impurities. The pH of the aqueous layer was adjusted to 2-3using 1.5N HCl. The product was extracted with EtOAc. The organic layerwas dried over anhydrous sodium sulfate and the solvent was removedunder reduced pressure to yield 3-cyano-5-ethylbenzoic acid (200 mg,yield 80%), which was carried through without further purification. ¹HNMR (400 MHz, CDCl₃) δ 8.23 (m, 1H), 8.17 (m, 1H), 7.74 (m, 1H), 2.81(q, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H).

3-Ethyl-5-(N′-hydroxycarbamimidoyl)benzoic acid

This compound was synthesized from 3-cyano-5-ethylbenzoic acid asdescribed in example 1 step 4 (200 mg, crude), and it was carriedthrough without further purification.

3-Ethyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

This compound was synthesized from3-ethyl-5-(N′-hydroxycarbamimidoyl)benzoic acid as described in example1 step 5 (130 mg, yield 52%). ¹H NMR (300 MHz, CDCl₃) δ 8.69 (m, 1H),8.21 (m, 1H), 8.17 (m, 1H), 2.85 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz,3H). MS (ESI) m/z: Calculated for C₁₂H₉F₃N₂O₃: 286.06; found: 285.0(M−H)⁻.

3-Ethyl-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-ethyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (85 mg, yield 45%). ¹H NMR (400 MHz,CDCl₃) δ 8.29 (s, 1H), 8.05 (s, 1H), 7.89 (m, 2H), 7.80 (s, 1H), 7.52(m, 2H), 7.37-7.29 (m, 3H), 4.00-3.94 (m, 2H), 3.89 (d, J=5.5 Hz, 2H),3.78-3.72 (ddd, J=11.7 Hz, 7.8 Hz, 3.3 Hz, 2H), 2.69 (q, J=7.7 Hz, 2H),2.36-2.30 (ddd, J=13.6 Hz, 6.5 Hz, 3.3 Hz, 2H), 2.08-2.02 (ddd, J=13.6Hz, 7.7 Hz, 3.3 Hz, 2H), 1.23 (t, J=7.7 Hz, 3H). MS (ESI) m/z:Calculated for C₂₇H₂₅F₃N₄O₃S: 542.16; found: 543.2 (M+H)⁺.

Example 34 4-(3-Bromophenyl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from 2-(3-bromophenyl)acetonitrile asdescribed in example 1 step 2 (1.3 g, 65% yield). MS (ESI) m/z:Calculated for C₁₂H₁₂BrNO: 265.01; found: 266.0 (M+H)⁺.

(4-(3-Bromophenyl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(3-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile as described inexample 1 step 3 (1.3 g, crude), and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₂H₁₆BrNO: 269.04;found: 270.0 (M+H)⁺.

N-((4-(3-Bromophenyl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(3-bromophenyl)tetrahydro-2H-pyran-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (40 mgs, 34% yield). ¹H NMR (300 MHz, CDCl₃) δ8.30-8.22 (m, 2H) 7.86 (d, J=3.7 Hz, 1H), 7.60 (t, J=3.7 Hz, 1H),7.52-7.44 (m, 2H), 7.38-7.30 (m, 2H), 3.90 (m, 2H), 3.71 (d, J=3.3 Hz,2H), 3.64 (m, 2H), 2.13 (m, 2H), 2.02 (m, 2H). MS (ESI) m/z: Calculatedfor C₂₂H₁₉BrF₃N₃O₃: 509.06; found: 509.9 (M+H)⁺.

Example 35 2-(4-(4-(Trifluoromethyl)phenyl)thiazol-2-yl)acetonitrile

This compound was synthesized from2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone and 2-cyanothioacetamideas described in example 1 step 1 (2.4 g, 48% yield), and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₁₂H₇F₃N₂S: 268.03; found: 269.0 (M+H)⁺.

4-(4-(4-(Trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)acetonitrile as describedin example 1 step 2 (690 mg, yield 98%), and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₆H₁₃F₃N₂OS:338.07; found: 339.1 (M+H)⁺.

(4-(4-(4-(Trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrileas described in example 1 step 3. The material was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₆H₁₇F₃N₂OS:342.10; found: 343.1 (M+H)⁺.

3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

This compound was synthesized from(4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (9 mgs, 19% yield). ¹H NMR (300 MHz,CDCl₃) δ 8.44 (s, 1H), 8.24 (d, J=7.7 Hz, 1H), 8.00 (m, 2H), 7.65-7.58(m, 4H), 7.36 (s, 1H), 4.02-3.78 (m, 4H), 3.74 (m, 2H), 2.30 (m, 2H),2.05 (m, 2H). MS (ESI) m/z: Calculated for C₂₆H₂₀F₆N₄O₃S: 582.12; found:583.1 (M+H)⁺.

Example 362-Methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propanenitrile

This compound was synthesized from2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)acetonitrile usingiodomethane as described in example 1 step 2 (620 mg, yield 73%) and itwas carried through without further purification. MS (ESI) m/z:Calculated for C₁₄H₁₁F₃N₂S: 296.06; found: 297.0 (M+H)⁺.

2-Methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-amine

This compound was synthesized from2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propanenitrile asdescribed in example 1 step 3. The material was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₄H₁₅F₃N₂S: 300.09;found: 301.1 (M+H)⁺.

N-(2-Methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (10 mgs, 24% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.51 (s,1H), 8.25 (d, J=7.4 Hz, 1H), 8.09-7.96 (m, 4H), 7.64-7.53 (m, 3H), 3.82(bs, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C₂₄H₁₈F₆N₄O₂S:540.11; found: 541.1 (M+H)⁺.

Example 37 1-(2-Ethoxy-2-oxoethyl)tetrahydro-1H-thiophenium bromide

Tetrahydrothiophene (10 g, 113 mmol) and ethyl bromoacetate (13 mL, 113mmol) were taken in acetone (50 mL) and stirred at room temperature for3 days. The precipitate was filtered, washed with acetone and air driedto get 1-(2-ethoxy-2-oxoethyl)tetrahydro-1H-thiophenium bromide (23 g,yield 82%), which was carried through without further purification.

Ethyl 2-cyanocyclopropanecarboxylate

50% KOH solution (16 mL) and saturated K₂CO₃ solution (60 mL) were addedto a cooled solution of compound get1-(2-ethoxy-2-oxoethyl)tetrahydro-1H-thiophenium bromide (23 g, 90 mmol)in CHCl₃ (70 mL). The mixture was stirred at 0° C. for 1 h. The organiclayer was separated and the aqueous layer was further extracted withCHCl₃. The combined organic extracts were dried over anhydrous sodiumsulfate and the solvent was removed under reduced pressure to get thezwitterionic intermediate (11 g, yield 76%). This crude intermediate wasdissolved in CHCl₃ (100 mL) and cooled to 0° C. Acrylonitrile (4 mL,68.3 mmol) was added to the reaction mixture and the mixture was furtherstirred at room temperature for 48 h. The solvent was evaporated underreduced pressure and the crude product was purified by columnchromatography (silica 60-120 mesh, eluent 30% EtOAc in petroleum ether)to get ethyl 2-cyanocyclopropanecarboxylate (5 g, yield 53%). ¹H NMR(300 MHz, CDCl₃) δ 4.19 (q, J=7.0 Hz, 2H), 2.29-2.23 (ddd, J=8.8 Hz, 6.0Hz, 4.3 Hz, 1H), 1.96-1.91 (ddd, J=9.1 Hz, 6.4 Hz, 4.3 Hz, 1H),1.56-1.45 (m, 2H), 1.30 (t, J=7.0 Hz, 3H)

2-Cyanocyclopropanecarboxylic acid

Ethyl 2-cyanocyclopropanecarboxylate (5 g, 35.9 mmol) was dissolved inMeOH (20 mL) and 1N NaOH (35 mL) was added. The reaction mixture wasstirred at room temperature for 2 h. After completion of the reactionMeOH was evaporated under reduced pressure. The pH of the aqueous layerwas adjusted to 2-3 using 1.5N HCl. The white precipitate was collectedby filtration and dried under reduced pressure to get2-cyanocyclopropanecarboxylic acid (3.3 g, yield 85%): ¹H NMR (400 MHz,DMSO-d₆) δ 12.78 (br s, 1H), 2.26-2.21 (ddd, J=8.8 Hz, 6.0 Hz, 4.3 Hz,1H), 2.14-2.09 (ddd, J=9.4 Hz, 6.2 Hz, 4.4 Hz, 1H), 1.53-1.48 (m, 1H),1.36-1.32 (m, 1H). MS (ESI) m/z: Calculated for C₅H₅NO₂: 111.03; found:110.2 (M−H)⁻.

2-Cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)cyclopropanecarboxamide

This compound was synthesized from(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and2-cyanocyclopropanecarboxylic acid as described in example 8 step 6 (90mg, yield 29%): ¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.52-7.46 (m,3H), 7.41-7.37 (m, 1H), 6.72 (t, J=5.3 Hz, 1H), 3.92-3.86 (m, 2H),3.75-3.68 (m, 4H), 2.30-2.22 (dddd, J=13.2 Hz, 9.8 Hz, 6.5 Hz, 3.4 Hz,2H), 1.99-1.89 (m, 4H), 1.52-1.47 (ddd, J=9.1 Hz, 5.8 Hz, 4.6 Hz, 1H),1.38-1.33 (ddd, J=8.6 Hz, 6.1 Hz, 4.9 Hz, 1H). MS (ESI) m/z: Calculatedfor C₂₀H₂₁N₃O₂S: 367.14; found: 368.2 (M+H)⁺.

2-(N′-Hydroxycarbamimidoyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)cyclopropanecarboxamide

This compound was synthesized from2-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)cyclopropanecarboxamideas described in example 1 step 4 (90 mg, crude) and it was used carriedthrough without further purification. MS (ESI) m/z: Calculated forC₂₀H₂₄N₄O₃S: 400.16; found: 401.2 (M+H)⁺.

N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)cyclopropanecarboxamide

This compound was synthesized from2-(N′-hydroxycarbamimidoyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)cyclopropanecarboxamideas described in example 1 step 5 (45 mg, yield 45%): ¹H NMR (400 MHz,MeOD) δ 7.94 (m, 2H), 7.77 (s, 1H), 7.38 (m, 2H), 7.30 (m, 1H),3.92-3.88 (dt, J=12.0 Hz, 3.8 Hz, 2H), 3.61-3.50 (m, 4H), 2.55-2.48(ddd, J=9.2 Hz, 5.6 Hz, 4.0 Hz, 1H), 2.35 (d, J=13.8 Hz, 2H), 2.31-2.27(ddd, J=8.7 Hz, 5.7 Hz, 4.1 Hz, 1H), 2.02-1.94 (m, 2H), 1.51-1.47 (m,1H), 1.39-1.34 (m, 1H). MS (ESI) m/z: Calculated for C₂₂H₂₁F₃N₄O₃S:478.13; found: 479.2 (M+H)⁺.

Example 38 2-Chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride

1,5-Dichloroazapentane hydrochloride (1.0 g, 5.6 mmol) was taken informic acid (0.43 mL, 11.2 mmol). A formaldehyde solution (1.2 mL, 37%in water) was added and the reaction mixture was heated to 100° C. for 4h and then to 120° C. for 0.5 h. The reaction mixture was cooled to roomtemperature and the solvent was removed under reduced pressure. Thecrude mixture was washed with hexane to afford2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.0 g,yield 92%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 11.21 (br s,1H), 4.04-4.00 (t, J=6.8 Hz, 4H), 3.54-3.48 (m, 4H), 2.82 (s, 3H).

1-Methyl-4-(2-phenylthiazol-4-yl)piperidine-4-carbonitrile

This compound was synthesized from (2-phenyl-thiazol-4-yl)-acetonitrileand 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride asdescribed in example 16 step 1b (135 mg, yield 25%). ¹H NMR (300 MHz,CDCl3) δ 7.97-7.94 (m, 2H), 7.45-7.43 (m, 3H), 7.30 (s, 1H), 3.00-2.96(m, 2H), 2.53-2.40 (m, 7H), 2.25-2.20 (m, 2H). MS (ESI) m/z: Calculatedfor C₁₆H₁₇N₃S: 283.11; found: 284.2 (M+H)⁺.

(1-Methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methanamine

This compound was synthesized from1-methyl-4-(2-phenylthiazol-4-yl)piperidine-4-carbonitrile as describedin example 1 step 3 (110 mg) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₆H₂₁N₃S: 287.15; found:288.2 (M+H)⁺.

N-((1-Methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from(1-methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (15 mg, yield 8%). ¹H NMR (400 MHz, CDCl₃) δ 9.43(d, J=1.5 Hz, 1H), 9.22 (d, J=1.8 Hz, 1H), 8.76 (m, 1H), 7.92-7.90 (m,3H), 7.42-7.41 (m, 3H), 7.19 (s, 1H), 3.92-3.87 (m, 2H), 3.00 (m, 2H),2.84 (m, 2H), 2.57 (m, 5H), 2.25 (m, 2H). MS (ESI) m/z: Calculated forC₂₅H₂₃F₃N₆O₂S: 528.55; found: 529.2 (M+H)⁺.

Example 39 4-(Chloromethyl)-2-(4-chlorophenyl)thiazole

A mixture of 4-chlorothiobenzamide (0.5 g, 2.9 mmol) and1,3-dichloroacetone (0.4 g, 3.18 mmol) in EtOH-THF (20 mL-10 mL) washeated to 85° C. for 10 h. The reaction mixture was cooled to roomtemperature and quenched with 10% NaHCO₃ solution. The organic productwas extracted with EtOAc and the organic layer was washed with H₂O andbrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 3-5% EtOAc in petroleumether) to afford 4-(chloromethyl)-2-(4-chlorophenyl)thiazole (0.55 g,yield 77%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91-7.88 (m,2H), 7.44-7.41 (m, 2H), 7.33 (s, 1H), 4.75 (s, 2H). MS (ESI) m/z:Calculated for C₁₀H₇Cl₂NS: 242.97; found: 244.0 (M+H)⁺.

2-(2-(4-Chlorophenyl)thiazol-4-yl)acetonitrile

A catalytic amount of 18-crown-6-ether (20 mg) was added to a solutionof 4-(chloromethyl)-2-(4-chlorophenyl)thiazole (0.55 g, 2.25 mmol) inacetonitrile (20 mL), followed by potassium cyanide (0.22 g, 3.37 mmol)and the reaction mixture was refluxed for 10 h. The reaction mixture wasthen quenched with water and the organic product extracted with EtOAc.The combined extracts were washed with H₂O and brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by column chromatography (silica gel 60-120mesh, eluent 15% EtOAc in petroleum ether) to afford2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile (0.43 g, yield 82%) as anoff-white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.89-7.86 (d, J=8.6 Hz, 2H),7.45-7.42 (d, J=8.6 Hz, 2H), 7.32 (m, 1H), 3.96 (s, 2H). MS (ESI) m/z:Calculated for C₁₁H₇ClN₂S: 234.00; found: 235.0 (M+H)⁺.

2-(2-(4-Chlorophenyl)thiazol-4-yl)-2-methylpropanenitrile

This compound was synthesized from2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (0.15 g, yield 70%) as a pale yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 7.92-7.88 (d, J=8.6 Hz, 2H), 7.44-7.41(d, J=8.6 Hz, 2H), 7.29 (s, 1H), 1.82 (s, 6H). MS (ESI) m/z: Calculatedfor C₁₃H₁₁ClN₂S: 262.03; found: 263.0 (M+H)⁺.

2-(2-(4-Chlorophenyl)thiazol-4-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(2-(4-Chlorophenyl)thiazol-4-yl)-2-methylpropanenitrile as describedin example 1 step 3, (60 mg, yield 40%). ¹H NMR (400 MHz, CDCl₃) δ7.90-7.88 (d, J=8.6 Hz, 2H), 7.42-7.40 (d, J=8.6 Hz, 2H), 6.99 (s, 1H),2.98 (s, 2H), 1.39 (s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₅ClN₂S:266.06; found: 267.0 (M+H)⁺.

N-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (50 mg, yield 51%). ¹H NMR (400 MHz, CDCl₃) δ 9.46(d, J=1.5 Hz, 1H), 9.24 (d, J=1.8 Hz, 1H), 8.79 (m, 1H), 8.22 (t, J=4.5Hz, 1H), 7.85-7.83 (d, J=8.5 Hz, 2H), 7.38-7.36 (d, J=8.5 Hz, 2H), 7.09(s, 1H), 3.72 (d, J=5.5 Hz, 2H), 1.50 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₂H₁₇ClF₃N₅O₂S: 507.07; found: 508.0 (M+H)⁺.

Example 404-(2-(4-Chlorophenyl)thiazol-4-yl)-1-methylpiperidine-4-carbonitrile

This compound was synthesized from2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile and2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as describedin example 16 step 1 b (350 mg, yield 32%). ¹H NMR (300 MHz, CDCl₃) δ7.91-7.88 (d, J=8.6 Hz, 2H), 7.43-7.40 (d, J=8.6 Hz, 2H), 7.32 (s, 1H),3.03-2.98 (m, 2H), 2.57-2.38 (m, 7H), 2.26-2.21 (m, 2H). MS (ESI) m/z:Calculated for C₁₆H₁₆ClN₃S: 317.08; found: 318.2 (M+H)⁺.

(4-(2-(4-Chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamine

This compound was synthesized from4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidine-4-carbonitrile asdescribed in example 1 step 3 (130 mg, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₆H₂₀ClN₃S:321.11; found: 322.2 (M+H)⁺.

N-((4-(2-(4-Chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from(4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamineand 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid asdescribed in example 8 step 6 (17 mg, yield 11%). ¹H NMR (400 MHz, MeOD)δ 9.36 (d, J=2.0 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.72 (t, J=2.0 Hz,1H), 7.95-7.93 (d, J=8.5 Hz, 2H), 7.59 (br s, 1H), 7.44-7.42 (d, J=8.6Hz, 2H), 3.73 (m, 2H), 3.50-3.49 (m, 2H), 2.87-2.83 (m, 7H), 2.21-2.16(m, 2H). MS (ESI) m/z: Calculated for C₂₅H₂₂ClF₃N₆O₂S: 562.12; found:563.2 (M+H)⁺.

Example 41N-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (75 mg, yield 25%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (m,1H), 8.27-8.25 (m, 1H), 8.10-8.05 (m, 2H), 7.86-7.84 (d, J=8.5 Hz, 2H),7.62-7.59 (t, J=7.8 Hz, 1H), 7.33-7.31 (d, J=8.5 Hz, 2H), 7.08 (s, 1H),3.71-3.69 (d, J=5.3 Hz, 2H), 1.49 (s, 6H). MS (ESI) m/z: Calculated forC₂₃H₁₈ClF₃N₄O₂S: 506.08; found: 507.0 (M+H)⁺.

Example 42 2-(2-(4-Chlorophenyl)thiazol-4-yl)ethanamine

Borane dimethyl sulfide complex (0.24 mL, 2.5 mmol) was added to asolution of 2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile (150 mg, 0.63mmol) in dry THF (15 mL) at room temperature. The reaction mixture wasrefluxed for 0.5 h and then quenched carefully with methanol. Thereaction mixture was concentrated under reduced pressure and dilutedwith EtOAc. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford 2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine (150 mg, crude)which was used as such for the next step.

N-(2-(2-(4-Chlorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (13 mg, yield 23%). ¹H NMR (400 MHz, CDCl₃) δ 9.46(m, 1H), 9.25 (m, 1H), 8.81-8.80 (t, J=2 Hz, 1H), 7.87-7.84 (m, 2H),7.40-7.37 (m, 2H), 7.08 (s, 1H), 3.93-3.89 (m, 2H), 3.16-3.13 (m, 2H).MS (ESI) m/z: Calculated for C₂₀H₁₃ClF₃N₅O₂S: 479.04; found: 480.0(M+H)⁺.

Example 43 Methyl 2-cyanoisonicotinate

Trimethylsilyl cyanide (3.8 g, 0.0386 mol) and dimethylcarbamyl chloride(5.0 g, 0.0483 mol) were added to a solution of methylisonicotinateN-oxide (5.0 g, 0.0322 mol) in dry CH₂Cl₂ (50 mL) at room temperature.The reaction mixture was stirred at room temperature for 12 h and thenquenched with 10% K₂CO₃ solution. The organic product was extracted withCH₂Cl₂ and the organic layer was washed with H₂O and brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography (silica 230-400mesh, eluent 1-2% MeOH in CH₂Cl₂) to afford methyl 2-cyanoisonicotinate(1.75 g, yield 33%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.97-8.95 (d, J=5.0 Hz, 1H), 8.41 (m, 1H), 8.15-8.13 (dd, J=4.8 Hz, 1.6Hz, 1H), 3.92 (s, 3H).

2-Cyanoisonicotinic acid

Lithium hydroxide (96 mg, 4.0 mmol) was added to a solution of methyl2-cyanoisonicotinate (0.6 g, 3.7 mmol) in THF-H₂O (20 mL, 7:3 v/v) at 0°C. The reaction mixture was allowed to warm up to room temperature andfurther stirred for 1 h. The reaction mixture was concentrated underreduced pressure and then diluted with water. The aqueous layer waswashed with EtOAc. The pH of the aqueous layer was adjusted to ˜3 using1.5N HCl and the organic product was extracted with EtOAc. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 2-cyanoisonicotinic acid (490 mg, yield 89%) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆) δ 14.11 (br s, 1H), 8.93-8.91(dd, J=4.9 Hz, 0.8 Hz, 1H), 8.34 (d, J=0.9 Hz, 1H), 8.11-8.10 (m, 1H).MS (ESI) m/z: Calculated for C₇H₄N₂O₂: 148.03; found: 147.2 (M−H)⁻.

2-(N′-Hydroxycarbamimidoyl)isonicotinic acid

This compound was synthesized from 2-cyanoisonicotinic acid as describedin example 1 step 4 (500 mg, crude), which was carried through withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (br s, 1H),10.36 (br s, 2H), 10.13 (br s, 1H), 8.87-8.86 (d, J=4.9 Hz, 1H), 8.44(s, 1H), 7.99-7.98 (d, J=4.9 Hz, 1H). MS (ESI) m/z: Calculated forC₇H₇N₃O₃: 181.05; found: 182.2 (M+H)⁺.

2-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinic acid

This compound was synthesized from2-(N′-hydroxycarbamimidoyl)isonicotinic acid as described in example 1step 5 (200 mg, yield 23%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ14.11 (br s, 1H), 9.02-9.00 (dd, J=4.8 Hz, 0.7 Hz, 1H), 8.45 (m, 1H),8.09-8.07 (dd, J=5.0 Hz, 1.5 Hz, 1H). MS (ESI) m/z: Calculated forC₉H₄F₃N₃O₃: 259.02; found: 260.0 (M+H)⁺.

N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinamide

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinic acid asdescribed in example 8 step 6 (65 mg, yield 33%). ¹H NMR (400 MHz,CDCl₃) δ 8.94-8.92 (dd, J=5.0 Hz, 0.8 Hz, 1H), 8.50 (m, 1H), 8.39-8.36(t, J=5.6 Hz, 1H), 7.88-7.86 (dd, J=5.0 Hz, 1.5 Hz, 1H), 7.79-7.77 (d,J=8.5 Hz, 2H), 7.44 (s, 1H), 7.35-7.33 (d, J=8.5 Hz, 2H), 3.83-3.82 (d,J=5.8 Hz, 2H), 1.57 (s, 6H). MS (ESI) m/z: Calculated forC₂₂H₁₇ClF₃N₅O₂S: 507.07; found: 508.0 (M+H)⁺.

Example 44 4-(Chloromethyl)-2-(4-fluorophenyl)thiazole

This compound was synthesized from 4-fluorothiobenzamide and1,3-dichloroacetone as described in example 39 step 1 (0.65 g, yield89%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.96-7.93 (m, 2H), 7.30(s, 1H), 7.16-7.12 (t, J=8.7 Hz, 2H), 4.75 (s, 2H). MS (ESI) m/z:Calculated for C₁₀H₇ClFNS: 227.00; found: 228.0 (M+H)⁺.

2-(2-(4-Fluorophenyl)thiazol-4-yl)acetonitrile

This compound was synthesized from4-(chloromethyl)-2-(4-fluorophenyl)thiazole as described in example 39step 2 (0.27 g, yield 80%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.95-7.91 (m, 2H), 7.30 (s, 1H), 7.17-7.13 (t, J=8.7 Hz, 2H),3.95 (s, 2H). MS (ESI) m/z: Calculated for C₁₁H₇FN₂S: 218.03; found:219.0 (M+H)⁺.

2-(2-(4-Fluorophenyl)thiazol-4-yl)-2-methylpropanenitrile

This compound was synthesized from2-(2-(4-fluorophenyl)thiazol-4-yl)acetonitrile and methyl iodide asdescribed in example 1 step 2 (250 mg, yield 75%). ¹H NMR (400 MHz,CDCl₃) δ 7.98-7.94 (m, 2H), 7.41 (s, 1H), 7.17-7.12 (t, J=8.7 Hz, 2H),1.82 (s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₁FN₂S: 246.06; found:247.2 (M+H)⁺.

2-(2-(4-Fluorophenyl)thiazol-4-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanenitrile as describedin example 1 step 3 (200 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₃H₁₃FN₂S: 250.09;found: 251.2 (M+H)⁺.

N-(2-(2-(4-Fluorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (55 mg, yield 30%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (m,1H), 8.26-8.24 (d, J=7.8 Hz, 1H), 8.13-8.11 (m, 1H), 8.07-8.05 (d, J=7.5Hz, 1H), 7.92-7.89 (m, 2H), 7.62-7.58 (t, J=7.8 Hz, 1H), 7.06-7.02 (m,3H), 3.71-3.69 (d, J=5.3 Hz, 2H), 1.49 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₃H₁₈F₄N₄O₂S: 490.11; found: 491.0 (M+H)⁺.

Example 45N-(2-(2-(4-Fluorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (50 mg, yield 26%). ¹H NMR (400 MHz, MeOD) δ 9.36(d, J=2.0 Hz, 1H), 9.11 (d, J=2.3 Hz, 1H), 8.77-8.76 (t, J=2.1 Hz, 1H),8.00-7.96 (m, 2H), 7.30 (s, 1H), 7.18-7.14 (t, J=8.8 Hz, 2H), 3.75 (s,2H), 1.50 (s, 6H). MS (ESI) m/z: Calculated for C₂₂H₁₇F₄N₆O₂S: 491.10;found: 492.0 (M+H)⁺.

Example 46 6-((Benzyloxy)carbonyl)picolinic acid

A mixture of 2,6-pyridinedicarboxylic acid (10 g, 0.06 mol) and benzylalcohol (68 mL, 0.66 mol) were taken in water (25 mL), and concentratedH₂SO₄ (3.5 mL) was added. The reaction mixture was refluxed for 10 h andfurther allowed to stir at room temperature for 24 h. The reactionmixture was concentrated under reduced pressure and the organic productwas extracted with CHCl₃. The solvent was removed under reduced pressureand the crude product was purified by column chromatography (silica gel60-120 mesh, eluent 5% MeOH in CH₂Cl₂) to afford6-((benzyloxy)carbonyl)picolinic acid (4.6 g, yield 30%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (br s, 1H), 8.29-8.24 (m, 2H),8.20-8.16 (m, 1H), 7.52-7.50 (m, 2H), 7.44-7.36 (m, 3H), 5.43 (s, 2H).MS (ESI) m/z: Calculated for C₁₄H₁₁NO₄: 257.07; found: 258.2 (M+H)⁺.

6-Carbamoylpicolinic acid

A solution of 6-((benzyloxy)carbonyl)picolinic acid (3.0 g, 11.7 mmol)in saturated NH₄OH (100 mL) was heated in a sealed tube at 90° C. for 6h and monitored by TLC (CHCl₃/MeOH 8:2 v/v). The reaction mixture wasevaporated to dryness to get the 6-carbamoylpicolinic acid (1.8 g, yield94%) as a white solid, which was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₇H₆N₂O₃: 166.04; found:167.0 (M+H)⁺.

6-Cyanopicolinic acid

6-Carbamoylpicolinic acid (1.0 g, 6.0 mmol) was taken in phosphorusoxychloride (20 mL) and heated to reflux for 4 h. Excess POCl₃ wasremoved under reduced pressure and the residue was quenched with icewater. The organic product was extracted with EtOAc and the solvent wasremoved under reduced pressure to afford 6-cyanopicolinic acid (500 mg,yield 56%), which was carried through without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ 8.31-8.28 (m, 2H), 8.26-8.21 (m, 1H). MS (ESI)m/z: Calculated for C₇H₄N₂O₂: 148.03; found: 147.2 (M−H)⁻.

6-(N′-Hydroxycarbamimidoyl)picolinic acid

This compound was synthesized from 6-cyanopicolinic acid as described inexample 1 step 4 (500 mg, crude), which was carried through withoutfurther purification. ¹H NMR (400 MHz, D₂O) δ 8.31-8.29 (m, 1H),8.18-8.14 (t, J=7.8 Hz, 1H), 8.07-8.05 (m, 1H).

6-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinic acid

This compound was synthesized from 6-(N′-hydroxycarbamimidoyl)picolinicacid as described in example 1 step 5 (110 mg, yield 20%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (br s, 1H), 8.36-8.34(m, 1H), 8.27-8.25 (m, 2H). MS (ESI) m/z: Calculated for C₉H₄F₃N₃O₃:259.02; found: 260.0 (M+H)⁺.

N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinamide

This compound was synthesized from6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinic acid and2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine as describedin example 8 step 6 (55 mg, yield 56%). ¹H NMR (400 MHz, CDCl₃) δ8.87-8.85 (m, 1H), 8.43-8.41 (dd, J=7.8 Hz, 1 Hz, 1H), 8.27-8.24 (dd,J=7.8 Hz, 1.3 Hz, 1H), 8.10-8.06 (m, 1H), 7.89-7.87 (d, J=8.5 Hz, 2H),7.41 (s, 1H), 7.32-7.29 (d, J=8.8 Hz, 2H), 3.91-3.89 (d, J=6.5 Hz, 2H),1.56 (s, 6H). MS (ESI) m/z: Calculated for C₂₂H₁₇ClF₃N₅O₂S: 507.07;found: 508.0 (M+H)⁺.

Example 47 (4-Phenylthiazol-2-yl)methanol

Potassium hydroxide (1.06 g, 18.84 mmol) was added to an ice cooledsolution of benzoic acid (4-phenylthiazol-2-yl)methyl benzoate (3.71 g,12.56 mmol) in EtOH (40 mL). The reaction mixture was slowly warmed toroom temperature and allowed to stir for 1 h. The reaction mixture wasconcentrated under reduced pressure and then diluted with water. Theorganic product was extracted with EtOAc, washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Thecrude product was purified by column chromatography (silica 60-120 mesh,eluant 10% EtOAc in petroleum ether) to get the pure(4-phenylthiazol-2-yl)methanol (2.1 g, yield 87%). ¹H NMR (400 MHz,CDCl₃) δ 7.89-7.87 (m, 2H), 7.46-7.41 (m, 3H), 7.37-7.33 (m, 1H), 5.01(s, 2H). MS (ESI) m/z: Calculated for C₁₀H₉NOS: 191.04; found: 192.2(M+H)⁺.

4-Phenylthiazole-2-carbaldehyde

A solution of (4-phenylthiazol-2-yl)methanol (2.1 g, 10.98 mmol) in dryCH₂Cl₂ (50 mL) was purged with argon for 10 min and Dess-Martinperiodinane (7.0 g, 16.5 mmol) was added to the solution at 0° C. Thereaction mixture was allowed to warm up to room temperature and furtherstirred for 3 h (monitored by TLC, petroleum ether/EtOAc 8:2 v/v). Thereaction mixture was then quenched with saturated sodium thiosulfatesolution. The organic product was extracted with CH₂Cl₂, and the organiclayer was washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to yield aldehyde4-phenylthiazole-2-carbaldehyde (1.95 g, yield 94%), which was carriedthrough without further purification. ¹H NMR (300 MHz, CDCl₃) δ 10.08(m, 1H), 7.98-7.95 (m, 2H), 7.90 (m, 1H), 7.52-7.39 (m, 3H). MS (ESI)m/z: Calculated for C₁₀H₇NOS: 189.02; found: 190.0 (M+H)⁺.

2-(Dimethylamino)-2-(4-phenylthiazol-2-yl)acetonitrile

Sodium cyanide (124 mg, 2.53 mmol) was added to a solution ofdimethylamine hydrochloride (280 mg, 3.43 mmol) in water (10 mL),followed by the addition of a solution of4-phenylthiazole-2-carbaldehyde (400 mg, 2.11 mmol) in methanol (20 mL)while maintaining the temperature at ˜25° C. The reaction mixture wasfurther stirred for 4 h at same temperature, then it was diluted withwater and the organic product was extracted with EtOAc. The organiclayer was washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to get the crude product, which waspurified by column chromatography (silica 60-120 mesh, eluant 15% EtOAcin petroleum ether), to yield2-(dimethylamino)-2-(4-phenylthiazol-2-yl)acetonitrile (160 mg, yield31%). ¹H NMR (400 MHz, CDCl₃) δ 7.97-7.94 (m, 2H), 7.57 (s, 1H),7.46-7.42 (m, 2H), 7.38-7.33 (m, 1H), 5.12 (s, 1H), 2.50 (s, 6H). MS(ESI) m/z: Calculated for C₁₃H₁₃N₃S: 243.08; found: 244.2 (M+H)⁺.

N,N-Dimethyl-1-(4-phenylthiazol-2-yl)ethane-1,2-diamine

This compound was synthesized from2-(dimethylamino)-2-(4-phenylthiazol-2-yl)acetonitrile as described inexample 1 step 3 (130 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₃H₁₇N₃S: 247.11;found: 248.2 (M+H)⁺.

N-(2-(Dimethylamino)-2-(4-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized fromN,N-dimethyl-1-(4-phenylthiazol-2-yl)ethane-1,2-diamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (16 mg, yield 17%). ¹H NMR (400 MHz, CDCl₃) δ 8.57-8.56(t, J=1.5 Hz, 1H), 8.26-8.23 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.07-8.05 (dt,J=7.8 Hz, 1.4 Hz, 1H), 7.91-7.87 (m, 3H), 7.63-7.59 (t, J=7.8 Hz, 1H),7.51 (s, 1H), 7.42-7.38 (m, 2H), 7.36-7.31 (m, 1H), 4.35-4.29 (ddd,J=13.2 Hz, 6.6 Hz, 5.5 Hz, 1H), 4.15-4.12 (m, 1H), 3.85-3.78 (ddd,J=13.0 Hz, 8.3 Hz, 4.6 Hz, 1H), 2.51 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₃H₂₀F₃N₅O₂S: 487.13; found: 488.2 (M+H)⁺.

Example 48 2(3-Phenyl-1H-1,2,4-triazol-5-yl)ethanamine

Borane dimethyl sulfide complex (0.2 mL, 2.16 mmol) was added to asolution of compound 2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetonitrile (100mg, 0.54 mmol) in dry THF (5 mL) at room temperature. The reactionmixture was refluxed for 1 h, then quenched carefully with methanol andagain heated to reflux for 0.5 h. The reaction mixture was concentratedunder reduced pressure and then diluted with EtOAc. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethanamine (130 mg, crude), which wascarried through without further purification. MS (ESI) m/z: Calculatedfor C₁₀H₁₂N₄: 188.11; found: 189.2 (M+H)⁺.

N-(2-(3-Phenyl-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (17 mg, yield 21%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s,1H), 8.21-8.19 (d, J=7.8 Hz, 1H), 8.06-8.04 (t, J=7.8 Hz, 1H), 8.01-7.99(m, 2H), 7.89 (m, 1H), 7.58-7.54 (d, J=7.8 Hz, 1H), 7.40-7.39 (m, 3H),4.00-3.95 (q, J=5.9 Hz, 2H), 3.24-3.21 (d, J=6.1 Hz, 2H). MS (ESI) m/z:Calculated for C₂₀H₁₅F₃N₆O₂: 428.12; found: 429.2 (M+H)⁺.

Example 49 1-(4-Phenylthiazol-2-yl)cyclopropanecarbonitrile

Benzyltriethyl ammonium chloride (34 mg, 0.15 mmol) and 50% aqueous NaOHsolution (0.59 g dissolved in 1 mL of water) were added to a solution of2-(4-phenylthiazol-2-yl)acetonitrile (0.3 g, 1.5 mmol) in CH₂Cl₂ (10mL). The reaction mixture was cooled at 0° C. and 1,2-dibromoethane(0.15 mL, 1.79 mmol) was added dropwise. The reaction mixture wasallowed to warm up to room temperature and stirred for 10 h. Thereaction mixture was diluted with CH₂Cl₂ and the organic layer waswashed with H₂O and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel 60-120 mesh, eluent 5% EtOAc in petroleumether) to afford 1-(4-phenylthiazol-2-yl)cyclopropanecarbonitrile (0.14g, yield 41%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.86-7.83(m, 2H), 7.45-7.34 (m, 4H), 2.02-1.95 (m, 2H), 1.93-1.86 (m, 2H). MS(ESI) m/z: Calculated for C₁₃H₁₀N₂S: 226.06; found: 227.2 (M+H)⁺.

(1-(4-Phenylthiazol-2-yl)cyclopropyl)methanamine

This compound was synthesized from1-(4-phenylthiazol-2-yl)cyclopropanecarbonitrile as described in example1 step 3 (59 mg, yield 42%) as a pale yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 7.91-7.89 (m, 2H), 7.44-7.40 (m, 2H), 7.35-7.33 (m, 1H), 7.30(s, 1H), 3.11 (s, 2H), 1.26-1.24 (m, 2H), 1.11-1.09 (m, 2H). MS (ESI)m/z: Calculated for C₁₃H₁₄N₂S: 230.09; found: 231.2 (M+H)⁺.

N-((1-(4-Phenylthiazol-2-yl)cyclopropyl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(1-(4-phenylthiazol-2-yl)cyclopropyl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (47 mg, yield 49%). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s,1H), 8.25-8.23 (m, 2H), 8.09-8.07 (m, 1H), 7.90-7.88 (m, 2H), 7.63-7.59(t, J=7.9 Hz, 1H), 7.41-7.38 (m, 2H), 7.35-7.33 (m, 1H), 7.32 (s, 1H),3.93 (d, J=5.5 Hz, 2H), 1.42-1.39 (m, 2H), 1.23-1.20 (m, 2H). MS (ESI)m/z: Calculated for C₂₃H₁₇F₃N₄O₂S: 470.10; found: 471.0 (M+H)⁺.

Example 50 N′-Hydroxy-3-nitrobenzimidamide

This compound was synthesized from 3-nitrobenzonitrile as described inexample 1 step 4 (5.5 g, crude) and it was carried through withoutfurther purification. ¹H NMR (300 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.50 (d,J=1.3 Hz, 1H), 8.23-8.19 (m, 1H), 8.12-8.10 (m, 1H), 7.67 (t, J=8.0 Hz,1H), 6.09 (m, 2H). MS (ESI) m/z: Calculated for C₇H₇N₃O₃: 181.05; found:182.2 (M+H)⁺.

3-(3-Nitrophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole

This compound was synthesized from N′-hydroxy-3-nitrobenzimidamide asdescribed in example 1 step 5 (1.6 g, yield 56%) and it was carriedthrough without further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.72(t, J=1.9 Hz, 1H), 8.53-8.48 (m, 2H), 7.93 (t, J=8.0 Hz, 1H). MS (ESI)m/z: Calculated for C₉H₄F₃N₃O₃: 259.02; found: 260.0 (M+H)⁺.

3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline

Sodium dithionite (1.61 g, 9.2 mmol) and a catalytic amount oftetra-n-butylammonium bromide (20 mg) were added to a solution of3-(3-nitrophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (1.6 g, 6.1 mmol)in THF-H₂O (30 mL, 1:1 v/v), and the reaction mixture was stirred atroom temperature for 2 h and monitored by TLC (petroleum ether/EtOAc1:1). Solvent was removed under reduced pressure and the product wasextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude product was purified by column chromatography (silica gel60-120 mesh, eluent 30-35% EtOAc in petroleum ether) to afford3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline (0.8 g, yield 57%).¹H NMR (300 MHz, CDCl₃) δ 7.52-7.49 (dt, J=7.7 Hz, 1.2 Hz, 1H), 7.42 (m,1H), 7.30 (t, J=8.0 Hz, 1H), 6.89-6.86 (ddd, J=7.9 Hz, 2.4 Hz, 0.9 Hz,1H), 3.87 (br s, 2H). MS (ESI) m/z: Calculated for C₉H₆F₃N₃O: 229.05;found: 230.0 (M+H)⁺.

Methyl 4-amino-4-thioxobutanoate

Methyl succinamate (2 g, 15.2 mmol) was dissolved in dry THF (50 mL) andP₂S₅ (3.4 g, 15.2 mmol) was added and the reaction mixture was stirredat room temperature for 6 h. The reaction mixture was filtered through asintered funnel and the clear filtrate was concentrated under reducedpressure to get the crude product, which was further purified by columnchromatography (silica gel 60-120 mesh, eluent 50% EtOAc in petroleumether) to afford methyl 4-amino-4-thioxobutanoate (1.25 g, yield 53%) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.27 (br s, 2H), 3.72 (s, 3H),2.96-2.85 (m, 4H). MS (ESI) m/z: Calculated for C₅H₉NO₂S: 147.04; found:148.2 (M+H)⁺.

Ethyl 3-(4-(4-fluorophenyl)thiazol-2-yl)propanoate

A mixture of methyl 4-amino-4-thioxobutanoate (0.3 g, 2.03 mmol) and2-bromo-4-fluoroacetophenone (0.440 g, 2.03 mmol) in EtOH (10 mL) wasrefluxed for 3 h. The reaction mixture was cooled to room temperatureand solvent was removed under reduced pressure. The organic product wasextracted with EtOAc and the organic layer was washed with brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The crude product was purified by column chromatography (silica gel60-120 mesh, eluent 8-10% EtOAc in petroleum ether) to afford ethyl3-(4-(4-fluorophenyl)thiazol-2-yl)propanoate (0.45 g, crude containing7% of methyl ester product), which was carried through without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.83 (m, 2H), 7.28 (s, 1H),7.13-7.07 (t, J=8.8 Hz, 2H), 4.22-4.15 (q, J=7.0 Hz, 2H), 3.40-3.35 (t,J=7.3 Hz, 2H), 2.93-2.88 (t, J=7.3 Hz, 2H), 1.30-1.25 (t, J=7.1 Hz, 3H).MS (ESI) m/z: Calculated for C₁₄H₁₄FNO₂S: 279.07; found: 280.2 (M+H)⁺.

3-(4-(4-Fluorophenyl)thiazol-2-yl)propanoic acid

1N NaOH (5 mL) was added to an ice-cooled solution of crude ethyl3-(4-(4-fluorophenyl)thiazol-2-yl)propanoate (450 mg, 1.61 mmol) in MeOH(5 mL) and the solution was allowed to stir at room temperature for 1 h.Solvent was evaporated and the reaction mixture was diluted with water.The aqueous layer was washed with EtOAc and the pH of the aqueoussolution was adjusted to ˜2 using 1N HCl. The organic product wasextracted with EtOAc and the organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to yield3-(4-(4-fluorophenyl)thiazol-2-yl)propanoic acid (320 mg, yield 79%) asa white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.29 (br s, 1H), 7.99-7.96(m, 2H), 7.93 (s, 1H), 7.28-7.22 (t, J=9.0 Hz, 2H), 3.25-3.20 (t, J=7.1Hz, 2H), 2.78-2.74 (t, J=7.1 Hz, 2H). MS (ESI) m/z: Calculated forC₁₂H₁₀FNO₂S: 251.04; found: 252.2 (M+H)⁺.

3-(4-(4-Fluorophenyl)thiazol-2-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide

This compound was synthesized from3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline and3-(4-(4-fluorophenyl)thiazol-2-yl)propanoic acid as described in example8 step 6 (80 mg, yield 43%). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (br s, 1H),8.11 (s, 1H), 7.88-7.83 (m, 4H), 7.48-7.44 (t, J=7.9 Hz, 1H), 7.33 (s,1H), 7.14-7.10 (t, J=8.7 Hz, 2H), 3.52-3.48 (m, 2H), 3.04-3.01 (m, 2H).MS (ESI) m/z: Calculated for C₂₁H₁₄F₄N₄O₂S: 462.08; found: 463.0 (M+H)⁺.

Example 51N-(2-(2-(4-Chlorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (40 mg, yield 22%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (t,J=1.5 Hz, 1H), 8.27-8.25 (dt, J=7.8 Hz, 1.3 Hz, 1H), 8.09-8.07 (dt,J=7.8 Hz, 1.4 Hz, 1H), 7.89-7.87 (m, 2H), 7.68 (m, 1H), 7.62 (t, J=7.8Hz, 1H), 7.36-7.34 (m, 2H), 7.09 (s, 1H), 3.92-3.87 (m, 2H), 3.16 (t,J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C₂₁H₁₄ClF₃N₄O₂S: 478.05;found: 479.0 (M+H)⁺.

Example 52 N-((4-Phenylthiazol-2-yl)methyl)benzamide

A mixture of N-(2-amino-2-thioxoethyl)benzamide (300 mg, 1.54 mmol) and2-bromoacetophenone (305 mg, 1.54 mmol) in EtOH (10 mL) was heated to80° C. for 2 h. The reaction mixture was cooled to room temperature andthe solvent was evaporated under reduced pressure. The concentratedreaction mixture was diluted with EtOAc and the organic layer was washedwith H₂O and brine, and concentrated under reduced pressure to yieldN-((4-phenylthiazol-2-yl)methyl)benzamide (0.4 g, yield 88%) as a whitesolid, which was carried through without further purification. ¹H NMR(400 MHz, CDCl₃) δ 8.69 (br s, 1H), 8.04-8.01 (dd, J=7.8 Hz, 1.5 Hz,2H), 7.99-7.97 (m, 2H), 7.64 (s, 1H), 7.56-7.52 (m, 4H), 7.48-7.44 (m,2H), 5.34 (d, J=6 Hz, 2H). MS (ESI) m/z: Calculated for C₁₇H₁₄N₂OS:294.08; found: 295.0 (M+H)⁺.

(4-Phenylthiazol-2-yl)methanamine

6N HCl (4.5 mL) was added to a solution ofN-((4-phenylthiazol-2-yl)methyl)benzamide (150 mg, 0.51 mmol) in dioxane(10 mL) and the reaction mixture was stirred at 100° C. for 24 h(reaction monitored by TLC, eluant CHCl₃/MeOH). Reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inwater. The aqueous layer was washed twice with EtOAc. The pH of theaqueous layer was then adjusted to pH ˜9 using 10% NaHCO₃ and theorganic product was extracted with EtOAc. The organic layer was washedwith brine and concentrated under reduced pressure to yield(4-phenylthiazol-2-yl)methanamine (75 mg, yield 77%) as orange coloredliquid, which was carried through without further purification. ¹H NMR(300 MHz, CDCl₃) δ 7.91-7.88 (m, 2H), 7.45-7.40 (m, 3H), 7.36-7.31 (m,1H), 4.25 (br s, 2H), 3.79-3.75 (m, 1H), 3.68-3.63 (m, 1H). MS (ESI)m/z: Calculated for C₁₀H₁₀N₂S: 190.06; found: 191.2 (M+H)⁺.

N-((4-Phenylthiazol-2-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from (4-phenylthiazol-2-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (60 mg, yield 38%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.59 (m, 1H), 8.31-8.29 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.12-8.10(m, 1H), 7.91-7.89 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.44(t, J=7.5 Hz, 2H), 7.38-7.34 (m, 1H), 7.23 (t, J=4.8 Hz, 1H), 5.04 (d,J=5.5 Hz, 2H). MS (ESI) m/z: Calculated for C₂₀H₁₃F₃N₄O₂S: 430.07;found: 431.0 (M+H)⁺.

Example 53N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(4-(4-fluorophenyl)thiazol-2-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (50 mg, yield 29%). ¹H NMR (400 MHz, CDCl₃) δ 9.45(d, J=1.3 Hz, 1H), 9.24 (d, J=1.5 Hz, 1H), 8.80 (t, J=2.1 Hz, 1H),7.86-7.82 (m, 3H), 7.35 (s, 1H), 7.11-7.07 (m, 2H), 4.05-4.00 (q, J=5.7Hz, 2H), 3.41-3.38 (m, 2H). MS (ESI) m/z: Calculated for C₂₀H₁₃F₄N₅O₂S:463.07; found: 464.0 (M+H)⁺.

Example 54 2-(4-(4-Chlorophenyl)thiazol-2-yl)ethanamine

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)acetonitrile as described in example42 step 1 (400 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₁H₁₁ClN₂S: 238.03; found:239.0 (M+H)⁺.

N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (30 mg, yield 16%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s,1H), 8.26 (d, J=7.8 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.6 Hz,2H), 7.64-7.60 (m, 2H), 7.39 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 4.02-3.97(q, J=5.8 Hz, 2H), 3.39-3.36 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculatedfor C₂₁H₁₄ClF₃N₄O₂S: 478.05; found: 479.0 (M+H)⁺.

Example 55N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (65 mg, yield 35%). ¹H NMR (400 MHz, CDCl₃) δ 9.46(d, J=1.8 Hz, 1H), 9.24 (d, J=1.8 Hz, 1H), 8.80 (t, J=2.1 Hz, 1H),7.82-7.80 (m, 3H), 7.41 (s, 1H), 7.38-7.36 (m, 2H), 4.05-4.01 (q, J=5.8Hz, 2H), 3.43-3.40 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculated forC₂₀H₁₃ClF₃N₅O₂S: 479.04; found: 480.0 (M+H)⁺.

Example 564-(3,4-Dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-carbonitrile

3,4,5,6-Tetrahydro-4H-pyran-4-one (0.37 g, 3.75 mmol) was added to asolution of 1,2,3,4-tetrahydroisoquinoline (0.47 mL, 3.75 mmol) in conc.HCl (0.4 mL) diluted with ice water (1.5 mL), followed by a solution ofKCN (0.24 g, 3.75 mmol) dissolved in water (2 mL), and the reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas then diluted with water and the organic product was extracted withEtOAc. The organic layer was washed with H₂O and brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (silica 60-120 mesh, eluent 6%EtOAc in petroleum ether) to afford4-(3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-carbonitrile(300 mg, yield 33%). ¹H NMR (300 MHz, CDCl₃) δ 7.19-7.11 (m, 3H),7.07-7.05 (m, 1H), 4.10-4.04 (dt, J=12.3 Hz, 3.5 Hz, 2H), 3.87 (s, 2H),3.76-3.68 (m, 2H), 2.97-2.91 (m, 4H), 2.28-2.23 (dd, J=13.3 Hz, 1.4 Hz,2H), 1.93-1.84 (td, J=12.4 Hz, 4.2 Hz, 2H). MS (ESI) m/z: Calculated forC₁₅H₁₈N₂O: 242.14; found: 243.2 (M+H)⁺.

(4-(3,4-Dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-carbonitrile asdescribed in example 1 step 3 (80 mg, yield 26%). ¹H NMR (300 MHz,CDCl₃) δ 7.15-7.12 (m, 3H), 7.06-7.03 (m, 1H), 3.90 (s, 2H), 3.87-3.84(m, 2H), 3.65-3.58 (ddd, J=11.3 Hz, 8.1 Hz, 3.2 Hz, 2H), 2.94-2.85 (m,6H), 1.99-1.91 (m, 2H), 1.65-1.62 (m, 2H). MS (ESI) m/z: Calculated forC₁₅H₂₂N₂O: 246.17; found: 247.2 (M+H)⁺.

N-((4-(3,4-Dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (40 mg, yield 30%). ¹H NMR (400 MHz,CDCl₃) δ 8.45 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.91-7.89 (d, J=7.5 Hz,1H), 7.59-7.55 (t, J=7.8 Hz, 1H), 7.17-7.15 (m, 3H), 7.12-7.07 (m, 2H),3.96-3.93 (m, 4H), 3.86-3.85 (d, J=4.8 Hz, 2H), 3.74-3.68 (m, 2H), 2.95(m, 4H), 2.15-2.07 (m, 2H), 1.58-1.55 (m, 2H). MS (ESI) m/z: Calculatedfor C₂₅H₂₅F₃N₄O₃: 486.19; found: 487.2 (M+H)⁺.

Example 57N-Methyl-1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (300 mg,1.1 mmol) was dissolved in 1,2-dichloroethane (30 mL) and cooled to 0°C. Formaline solution (˜0.1 mL, 35%) was added to the solution, followedby sodiumtriacetoxy borohydride (0.16 g, 0.76 mmol). The reactionmixture was further stirred for 45 min maintaining the same temperature.The reaction mixture was then quenched with 10% NaHCO₃ solution anddiluted with CH₂Cl₂. The organic layer was separated, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by column chromatography (silica 60-120 mesh, eluent 10-20%MeOH in CHCl₃) to affordN-methyl-1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine(120 mg, yield 38%). ¹H NMR (300 MHz, CDCl₃) δ 7.90-7.88 (m, 2H), 7.48(s, 1H), 7.44-7.34 (m, 3H), 3.93-3.86 (m, 2H), 3.75-3.67 (ddd, J=12.0Hz, 8.9 Hz, 3.0 Hz, 2H), 3.01 (s, 2H), 2.49 (s, 3H), 2.36-2.39 (m, 2H),2.09-2.01 (m, 2H). MS (ESI) m/z: Calculated for C₁₆H₂₀N₂OS: 288.13;found: 289.2 (M+H)⁺.

N-Methyl-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized fromN-methyl-1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (30 mg, yield 14%). ¹H NMR (400 MHz,CDCl₃) δ 8.13-8.09 (m, 2H), 7.96-7.94 (m, 2H), 7.57-7.55 (m, 2H),7.48-7.41 (m, 3H), 7.36-7.32 (m, 1H), 3.99-3.96 (m, 2H), 3.92 (s, 2H),3.66-3.60 (m, 2H), 2.53 (s, 3H), 2.48-2.44 (m, 2H), 2.23-2.16 (m, 2H).MS (ESI) m/z: Calculated for C₂₆H₂₃F₃N₄O₃S: 528.14; found: 529.2 (M+H)⁺.

Example 58 2-(2-(4-Fluorophenyl)thiazol-4-yl)ethanamine

This compound was synthesized from2-(2-(4-fluorophenyl)thiazol-4-yl)acetonitrile as described in example42 step 1 (150 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₁H₁₁FN₂S: 222.06; found:223.0 (M+H)⁺.

N-(2-(2-(4-Fluorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-fluorophenyl)thiazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (30 mg, yield 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.45(br s, 1H), 9.26 (br s, 1H), 8.82 (t, J=2.0 Hz, 1H), 7.96-7.92 (m, 3H),7.14-7.08 (m, 3H), 3.94-3.89 (m, 2H), 3.19-3.16 (m, 2H). MS (ESI) m/z:Calculated for C₂₀H₁₃F₄N₅O₂S: 463.07; found: 464.0 (M+H)⁺.

Example 59N-(2-(2-(4-Fluorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)thiazol-4-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (60 mg, yield 45%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (t,J=1.4 Hz, 1H), 8.27-8.24 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.09-8.06 (dt,J=7.6 Hz, 1.6 Hz, 1H), 7.94-7.90 (m, 2H), 7.70 (m, 1H), 7.63-7.59 (t,J=7.8 Hz, 1H), 7.09-7.05 (m, 3H), 3.91-3.86 (m, 2H), 3.16-3.13 (t, J=6.0Hz, 2H). MS (ESI) m/z: Calculated for C₂₁H₁₄F₄N₄O₂S: 462.08; found:463.0 (M+H)⁺.

Example 60N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (55 mg, yield 42%). ¹H NMR (400 MHz, CDCl₃) δ 9.45(s, 1H), 9.24 (s, 1H), 8.79 (m, 1H), 8.25 (m, 1H), 7.85-7.81 (dd, J=8.6Hz, 5.4 Hz, 2H), 7.37 (s, 1H), 7.10-7.06 (t, J=8.6 Hz, 2H), 3.84 (d,J=5.6 Hz, 2H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C₂₂H₁₇F₄N₅O₂S:491.10; found: 492.0 (M+H)⁺.

Example 613-(2,2,2-Trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)imino)ethyl)benzonitrile

Triethylamine (1.0 mL, 2.7 mmol) was added to a solution of3-cyano-2,2,2-trifluoroacetophenone (0.48 g, 2.4 mmol) and(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (0.66 g,2.4 mmol) in dry CH₂Cl₂ (25 mL), followed by a solution of titaniumtetrachloride in CH₂Cl₂ (1.2 mL, 1.2 mmol, 1M solution in CH₂Cl₂) at 0°C. and the reaction mixture was warmed to room temperature and furtherstirred for 8 h. The reaction was concentrated under reduced pressureand the organic product was extracted with EtOAc. The organic layer waswashed with water and brine solution, dried over anhydrous sodiumsulfate and the solvent was removed under reduced pressure to get3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)imino)ethyl)benzonitrile(0.6 g, crude), which was carried through without further purification.¹H NMR (400 MHz, CDCl₃) δ 7.88-7.85 (m, 2H), 7.70-7.67 (m, 1H), 7.50 (s,1H), 7.46-7.41 (m, 3H), 7.39-7.36 (m, 0.1H), 7.23 (s, 1H), 7.07 (d,J=8.0 Hz, 1H), 3.93-3.88 (dt, J=11.9 Hz, 4.0 Hz, 2H), 3.66-3.62 (m, 4H),2.43-2.40 (m, 2H), 2.15-2.00 (ddd, J=14.1 Hz, 10.3 Hz, 4.3 Hz, 2H). MS(ESI) m/z: Calculated for C₂₄H₂₀F₃N₃OS: 455.13; found: 456.2 (M+H)⁺.

3-(2,2,2-Trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)benzonitrile

3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)imino)ethyl)benzonitrile(600 mg, 1.3 mmol) was dissolved in MeOH—H₂O (20 mL, 8:2 v/v) and cooledto 0° C. Sodium borohydride (250 mg, 6.6 mmol) was added to thissolution portionwise. The reaction mixture was allowed to warm up toroom temperature, stirred for 2 h, and then quenched with water andconcentrated under reduced pressure to remove the MeOH. The aqueousmixture was diluted with EtOAc and the organic layer was washed with H₂Oand brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluant 15-20% EtOAc in petroleumether) to afford3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)benzonitrile(300 mg, yield 50%). ¹H NMR (300 MHz, CDCl₃) δ 7.89-7.86 (m, 2H),7.63-7.60 (dt, J=7.6 Hz, 1.4 Hz, 1H), 7.55-7.51 (m, 2H), 7.50 (s, 1H),7.47-7.41 (m, 3H), 7.39-7.36 (m, 0.1H), 4.16-4.03 (m, 1H), 3.84-3.74 (m,2H), 3.71-3.61 (m, 2H), 2.95 (d, J=11.4 Hz, 1H), 2.76 (d, J=11.4 Hz,1H), 2.36-2.24 (m, 2H), 2.01-1.92 (ddd, J=13.5 Hz, 9.0 Hz, 4.1 Hz, 2H).MS (ESI) m/z: Calculated for C₂₄H₂₂F₃N₃OS: 457.14; found: 458.2 (M+H)⁺.

N′-Hydroxy-3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)benzimidamide

This compound was synthesized from3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)benzonitrileacid as described in example 1 step 4 (300 mg, crude), which was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₂₄H₂₆F₃N₄O₂S: 490.17; found: 491.2 (M+H)⁺.

2,2,2-Trifluoro-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-1-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)ethanamine

This compound was synthesized fromN′-hydroxy-3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)benzimidamideacid as described in example 1 step 5 (70 mg, yield 20%). ¹H NMR (400MHz, DMSO-d₆) δ 8.11-8.09 (dt, J=7.2 Hz, 1.7 Hz, 1H), 8.05 (s, 1H),7.85-7.83 (m, 2H), 7.53-7.49 (m, 2H), 7.47 (s, 1H), 7.42-7.38 (m, 2H),7.35-7.31 (m, 1H), 4.15-4.10 (q, J=7.2 Hz, 1H), 3.81-3.74 (m, 2H),3.70-3.62 (m, 2H), 2.99-2.96 (m, 1H), 2.86-2.83 (m, 1H), 2.33-2.27 (m,2H), 2.04-1.93 (ddd, J=13.4 Hz, 9.0 Hz, 4.0 Hz, 2H). MS (ESI) m/z:Calculated for C₂₆H₂₂F₆N₄O₂S: 568.14; found: 569.2 (M+H)⁺.

Example 62 Methyl 4-fluorobenzimidate hydrochloride

Dry HCl (g) was bubbled through a solution of 4-fluorobenzonitrile (5.0g, 0.041 mol) in dry MeOH—CH₂Cl₂ (20 mL, 1:1 v/v) until saturation. Theclear solution was kept at 0° C. for 2 days to crystallize methyl4-fluorobenzimidate as hydrochloride salt, which was isolated byfiltration (2.8 g, yield 36%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.95-7.92 (m,2H), 7.38 (br s, 1H), 7.29-7.25 (m, 2H), 3.06 (s, 3H). MS (ESI) m/z:Calculated for C₈H₈FNO: 153.06; found: 154.2 (M+H)⁺.

2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile

2-Cyanoacetohydrazide (172 mg, 1.74 mmol) and NaOH (66 mg, 1.66 mmol)were added to a solution of methyl 4-fluorobenzimidate hydrochloride(300 mg, 1.58 mmol) in dry MeOH (5 mL) and the mixture was heated toreflux for 1 h. The reaction mixture was concentrated under reducedpressure and the residue obtained was diluted with EtOAc. The organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica 60-120 mesh, eluant 20-25%EtOAc in petroleum ether) to yield2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile (150 mg, yield47%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.99 (m, 2H), 7.39-7.33 (m, 2H),4.11 (s, 2H). MS (ESI) m/z: Calculated for C₁₀H₇FN₄: 202.07; found:203.2 (M+H)⁺.

2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine

This compound was synthesized from2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile as described inexample 42 step 1 (40 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₀H₁₁FN₄: 206.10;found: 207.2 (M+H)⁺.

N-(2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (11 mg, yield 13%). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s,1H), 8.26-8.24 (d, J=7.8 Hz, 1H), 8.07-8.03 (m, 3H), 7.67-7.59 (m, 2H),7.13-7.09 (t, J=8.7 Hz, 2H), 4.01-3.96 (q, J=5.9 Hz, 2H), 3.24-3.21 (d,J=6.1 Hz, 2H). MS (ESI) m/z: Calculated for C₂₀H₁₄F₄N₆O₂: 446.11; found:447.2 (M+H)⁺.

Example 63 Methyl 4-chlorobenzimidate hydrochloride

This compound was synthesized from 4-chlorobenzonitrile as described inexample 62 step 1 (3.5 g, 47%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.95-7.92(m, 2H), 7.38 (br s, 1H), 7.29-7.25 (m, 2H), 3.06 (s, 3H). MS (ESI) m/z:Calculated for C₈H₈ClNO: 169.02; found: 170.0 (M+H)⁺.

2-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile

This compound was synthesized from methyl 4-chlorobenzimidatehydrochloride as described in example 62 step 2 (200 mg, yield 38%). ¹HNMR (300 MHz, CDCl₃) δ 7.87-7.84 (m, 1H), 7.63-7.60 (m, 1H), 7.51-7.47(m, 2H), 3.96 (s, 2H). MS (ESI) m/z: Calculated for C₁₀H₇ClN₄: 218.04;found: 219.0 (M+H)⁺.

2-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine

This compound was synthesized from2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile as described inexample 42 step 1 (90 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₀H₁₁ClN₄: 222.07;found: 223.2 (M+H)⁺.

N-(2-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (15 mg, yield 13%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s,1H), 8.28-8.26 (d, J=7.8 Hz, 1H), 8.09-8.06 (m, 1H), 8.02-8.00 (d, J=8.5Hz, 2H), 7.65-7.61 (t, J=7.8 Hz, 1H), 7.56-7.53 (m, 1H), 7.42-7.40 (d,J=8.5 Hz, 2H), 4.03-3.96 (q, J=6.0 Hz, 2H), 3.25-3.22 (d, J=6.0 Hz, 2H).MS (ESI) m/z: Calculated for C₂₀H₁₄ClF₃N₆O₂: 462.08; found: 463.0(M+H)⁺.

Example 64 Methyl 2-cyano-2-methylpropanoate

NaH (15.5 g, 60% dispersion in oil) was added portionwise over 10 min tothe solution of ethyl cyanoacetate (20 g, 0.177 mol) in dry DMF (300 mL)at 0° C. The resulting reaction mixture was stirred at room temperaturefor 30 min and cooled again to 0° C. Methyl iodide (28 mL, 0.44 mol) inTHF (50 mL) was added dropwise and the reaction mixture was stirred atroom temperature for 12 h, and then quenched with saturated NH₄CIsolution. The mixture was then diluted with EtOAc; the organic layer waswashed with H₂O and brine, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure to afford crude product that was purified bycolumn chromatography (silica gel 60-120 mesh, eluent 5% EtOAc inpetroleum ether) to afford methyl 2-cyano-2-methylpropanoate (12 g,yield 48%) as a pale yellow solid.

2-Cyano-2-methylpropanehydrazide

Hydrazine hydrate (1.8 mL, 35 mmol) was added to a solution of methyl2-cyano-2-methylpropanoate (5.0 g, 35.0 mmol) in EtOH (5 mL), and thereaction mixture was stirred at room temperature for 1 h (monitored byTLC, eluant petroleum ether:EtOAc 7:3 v/v). The reaction mixture wasdiluted with diethyl ether and the precipitate formed was filtered. Theclear filtrate was concentrated under reduced pressure to get2-cyano-2-methylpropanehydrazide (1.75 g, yield 38%), which was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₅H₉N₃O: 127.07; found: 128.2 (M+H)⁺.

2-Methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propanenitrile

2-Cyano-2-methylpropanehydrazide (100 mg, 0.78 mmol) and Et₃N (0.1 mL,0.86 mmol) were added to a solution of methyl benzimidate hydrochloride(100 mg, 0.58 mmol) in dry MeOH (10 mL), and the mixture was heated toreflux for 1 h. The reaction mixture was then concentrated under reducedpressure and the crude product was purified by column chromatography(silica 60-120 mesh, eluant 15% EtOAc in petroleum ether) to get2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propanenitrile (80 mg, yield51%). ¹H NMR (300 MHz, MeOD) δ 7.98-7.95 (m, 2H), 7.52-7.50 (m, 3H),1.82 (s, 6H). MS (ESI) m/z: Calculated for C₁₂H₁₂N₄: 212.11; found:213.2 (M+H)⁺.

2-Methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine

DIBAL-H (0.75 mL, 0.75 mmol, 1M in THF) was added to a solution of2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propanenitrile (80 mg, 0.37mmol) in dry THF (5 mL) at 0° C. The reaction mixture was allowed towarm up to room temperature and further stirred for 2 h. The reactionmixture was then quenched carefully with water and diluted with EtOAc.The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine (70 mg,crude), which was carried through without further purification. MS (ESI)m/z: Calculated for C₁₂H₁₆N₄: 216.14; found: 217.2 (M+H)⁺.

N-(2-Methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (35 mg, yield 25%). ¹H NMR (400 MHz, MeOD) δ 8.55 (s,1H), 8.29-8.27 (d, J=7.8 Hz, 1H), 8.06-7.97 (m, 3H), 7.71-7.67 (t, J=8.7Hz, 1H), 7.50-7.41 (m, 3H), 3.75 (s, 2H), 1.54-1.51 (m, 6H). MS (ESI)m/z: Calculated for C₂₂H₁₉F₃N₆O₂: 456.15; found: 457.2 (M+H)⁺.

Example 65N-(2-Methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (20 mg, yield 23%). ¹H NMR (400 MHz, MeOD) δ 9.37(m, 1H), 9.16 (m, 1H), 8.84-8.13 (m, 1H), 8.02-7.99 (m, 2H), 7.48-7.42(m, 3H), 3.77 (s, 2H), 1.54 (m, 6H). MS (ESI) m/z: Calculated forC₂₁H₁₈F₃N₇O₂: 457.15; found: 458.2 (M+H)⁺.

Example 662-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropanenitrile

This compound was synthesized from 2-cyano-2-methylpropanehydrazide andmethyl 4-fluorobenzimidate hydrochloride as described in example 64 step3 (300 mg, yield 70%). ¹H NMR (300 MHz, MeOD) δ 8.03-7.98 (m, 2H),7.29-7.23 (m, 2H), 1.81 (s, 6H). MS (ESI) m/z: Calculated for C₁₂H₁₁FN₄:230.10; found: 231.2 (M+H)⁺.

2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropanenitrile asdescribed in example 64 step 4 (200 mg, crude) and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₁₂H₁₅FN₄: 234.13; found: 235.2 (M+H)⁺.

N-(2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (12 mg, yield 7%). ¹H NMR (400 MHz, MeOD) δ 8.54 (s,1H), 8.29-8.27 (d, J=7.8 Hz, 1H), 8.05-8.03 (m, 3H), 7.71-7.67 (t, J=7.8Hz, 1H), 7.27-7.13 (m, 2H), 3.74 (s, 2H), 1.53-1.50 (m, 6H). MS (ESI)m/z: Calculated for C₂₂H₁₈F₄N₆O₂: 474.14; found: 475.2 (M+H)⁺.

Example 67N-(2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (20 mg, yield 11%). ¹H NMR (400 MHz, MeOD) δ9.38-9.37 (d, J=1.5 Hz, 1H), 9.15 (d, J=1.5 Hz, 1H), 8.82 (m, 1H),8.06-8.02 (m, 2H), 7.21-7.17 (t, J=8.5 Hz, 2H), 3.76 (s, 2H), 1.53 (s,6H). MS (ESI) m/z: Calculated for C₂₁H₁₇F₄N₇O₂: 475.14; found: 476.2(M+H)⁺.

Example 682-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropanenitrile

This compound was synthesized from 2-cyano-2-methylpropanehydrazide andmethyl 4-chlorobenzimidate hydrochloride as described in example 64 step3 (220 mg, yield 55%). ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.91 (m, 2H),7.47-7.45 (m, 2H), 1.86 (s, 6H). MS (ESI) m/z: Calculated forC₁₂H₁₁ClN₄: 246.07; found: 245.2 (M−H)⁻.

2-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropanenitrile asdescribed in example 64 step 4 (140 mg, crude) and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₁₂H₁₅ClN₄: 250.10; found: 251.2 (M+H)⁺.

N-(2-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (15 mg, yield 8%). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s,1H), 8.30-8.28 (d, J=8.0 Hz, 1H), 8.14-8.12 (m, 1H), 8.06-8.04 (d, J=8.3Hz, 2H), 7.93 (br s, 1H), 7.67-7.63 (t, J=7.7 Hz, 1H), 7.43-7.41 (d,J=8.5 Hz, 2H), 3.83-3.82 (m, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₂H₁₈ClF₃N₆O₂: 490.11; found: 491.2 (M+H)⁺.

Example 69 Ethyl 5-cyano-6-methylnicotinate

Ammonium chloride (3.58 g, 66.7 mmol in 10 mL water) was added to asolution of ethyl 2-chloro-5-cyano-6-methylnicotinate (1.0 g, 4.4 mmol)in dioxane-THF-DMF (50 mL, 3:1:1), followed by zinc powder (2.3 g, 35.6mmol) portionwise at room temperature. The reaction mixture was allowedto stir at room temperature for 3 h, diluted with EtOAc, and filteredthrough a pad of Celite. The clear filtrate of organic layer was washedwith H₂O and brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica 60-120 mesh, eluent 10-15% EtOAc in petroleumether) to afford ethyl 5-cyano-6-methylnicotinate (230 mg, yield 27%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.25 (d, J=2.0 Hz, 1H), 8.49(d, J=2.0 Hz, 1H), 7.27 (s, 1H), 4.47-4.42 (q, J=7.2 Hz, 2H), 2.86 (s,3H), 1.45-1.41 (t, J=7.0 Hz, 3H). MS (ESI) m/z: Calculated forC₁₀H₁₀N₂O₂: 190.07; found: 191.2 (M+H)⁺.

5-Cyano-6-methylnicotinic acid

This compound was synthesized from ethyl 5-cyano-6-methylnicotinate asdescribed in example 43 step 2 (150 mg, yield 76%) as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 13.77 (br s, 1H), 9.13-9.12 (d, J=2.0 Hz, 1H),8.61-8.60 (d, J=2.0 Hz, 1H), 2.74 (s, 3H). MS (ESI) m/z: Calculated forC₈H₆N₂O₂: 162.04; found: 161.2 (M+H)⁺.

5-(N′-Hydroxycarbamimidoyl)-6-methylnicotinic acid

This compound was synthesized from 5-cyano-6-methylnicotinic acid asdescribed in example 1 step 4 (130 mg, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₈H₉N₃O₃:195.06; found: 196.2 (M+H)⁺.

6-Methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid

This compound was synthesized from5-(N′-hydroxycarbamimidoyl)-6-methylnicotinic acid as described inexample 1 step 5 (25 mg, yield 15%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 13.71 (br s, 1H), 9.14-9.13 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2Hz, 1H), 2.86 (s, 3H). MS (ESI) m/z: Calculated for C₁₀H₆F₃N₃O₃: 273.04;found: 274.0 (M+H)⁺.

N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and6-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid asdescribed in example 8 step 6 (28 mg, yield 59%). ¹H NMR (400 MHz,CDCl₃) δ 9.11 (br s, 1H), 8.80 (br s, 1H), 8.07 (br s, 1H), 7.79-7.77(d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.35-7.33 (d, J=8.8 Hz, 2H), 3.86-3.84(d, J=5.5 Hz, 2H), 3.02 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₃H₁₉ClF₃N₅O₂S: 521.09; found: 522.0 (M+H)⁺.

Example 70 Methyl 4-amino-4-thioxobutanoate

A solution of methyl succinamate (2.5 g, 0.019 mol) in THF (60 mL) wascooled to 0° C. and P₂S₅ (4.2 g, 0.019 mol) was added. The reactionmixture was warmed to room temperature and stirred for 6 h. The solventwas removed under reduced pressure and the crude product was purified bycolumn chromatography (silica gel 60-120 mesh, eluent 35-40% EtOAc inpetroleum ether) to afford methyl 4-amino-4-thioxobutanoate (1.6 g,yield 57%). ¹H NMR (300 MHz, CDCl₃) δ 7.49 (br s, 2H), 3.72 (s, 3H),2.95-2.86 (m, 4H). MS (ESI) m/z: Calculated for C₅H₉NO₂S: 147.04; found:248.2 (M+H)⁺.

Ethyl 3-(4-phenylthiazol-2-yl)propanoate

A mixture of 2-bromo acetophenone (2.1 g, 10.55 mmol) and methyl4-amino-4-thioxobutanoate (1.6 g, 10.86 mmol) in EtOH (15 mL) was heatedto 80° C. for 3 h. Reaction mixture was cooled to room temperature andsolvent was evaporated under reduced pressure. The product was extractedwith EtOAc and the organic layer was washed with H₂O and brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure to affordethyl 3-(4-phenylthiazol-2-yl)propanoate (1.1 g, yield 40%) as a whitesolid, which was carried through without further purification. ¹H NMR(300 MHz, CDCl₃) δ 7.90-7.87 (m, 2H), 7.44-7.39 (m, 2H), 7.35-7.30 (m,2H), 4.22-4.15 (q, J=7.2 Hz, 2H), 3.41-3.36 (t, J=7.5 Hz, 2H), 2.94-2.89(t, J=7.3 Hz, 2H), 1.30-1.25 (t, J=7.1 Hz, 3H). MS (ESI) m/z: Calculatedfor C₁₄H₁₅NO₂S: 261.08; found: 262.2 (M+H)⁺.

3-(4-Phenylthiazol-2-yl)propan-1-ol

A solution of ethyl 3-(4-phenylthiazol-2-yl)propanoate (0.5 g, 1.91mmol) in MeOH—H₂O (10 mL, 9:1 v/v) was cooled to 0° C. and sodiumborohydride (0.29 g, 7.65 mmol) was added. The reaction mixture waswarmed to room temperature and further stirred for 8 h. The mixture wasquenched with ice water and the organic product was extracted withEtOAc. The combined extracts were washed with H₂O and brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to afford3-(4-phenylthiazol-2-yl)propan-1-ol (0.4 g, yield 95%) as colorlessliquid, which was carried through without further purification. ¹H NMR(400 MHz, CDCl₃) δ 7.87-7.85 (m, 2H), 7.44-7.40 (m, 2H), 7.35-7.32 (m,2H), 3.83-3.81 (t, J=5.8 Hz, 2H), 3.24-3.21 (m, 3H), 2.14-2.08 (m, 2H).MS (ESI) m/z: Calculated for C₁₂H₁₃NOS: 219.07; found: 220.2 (M+H)⁺.

3-(4-Phenylthiazol-2-yl)propyl methanesulfonate

A solution of 3-(4-phenylthiazol-2-yl)propan-1-ol (0.4 g, 1.82 mmol) indry pyridine (8 mL) was cooled to 0° C. and methanesulfonyl chloride(0.43 mL, 5.47 mmol) was added dropwise. The reaction mixture wasallowed to warm up to room temperature, stirred for 1 h, and quenchedwith ice water. The organic product was extracted with EtOAc and organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to afford3-(4-phenylthiazol-2-yl)propyl methanesulfonate (0.4 g, yield 74%) as apale yellow liquid, which was carried through without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 7.90-7.87 (m, 2H), 7.46-7.40 (m,2H), 7.37-7.31 (m, 2H), 4.42-4.38 (t, J=6.1 Hz, 2H), 3.24-3.19 (t, J=7.2Hz, 2H), 3.04 (s, 3H), 2.39-2.30 (m, 2H). MS (ESI) m/z: Calculated forC₁₃H₁₅NO₃S₂: 297.05; found: 298.0 (M+H)⁺.

2-(3-Azidopropyl)-4-phenylthiazole

Sodium azide (263 mg, 4.05 mmol) was added to a solution of3-(4-phenylthiazol-2-yl)propyl methanesulfonate (0.4 g, 1.35 mmol) indry DMF (8 mL), and the reaction mixture was heated to 100° C. for 2 h.The mixture was allowed to cool down to room temperature and dilutedwith EtOAc. The organic product was extracted with EtOAc and the organiclayer was washed with H₂O and brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to afford2-(3-azidopropyl)-4-phenylthiazole (0.3 g, yield 91%) as a pale orangeliquid, which was carried through without further purification. ¹H NMR(300 MHz, CDCl₃) δ 7.91-7.89 (m, 2H), 7.46-7.41 (m, 2H), 7.36-7.31 (m,2H), 3.49-3.44 (t, J=6.7 Hz, 2H), 3.20-3.15 (t, J=7.5 Hz, 2H), 2.21-2.12(m, 2H). MS (ESI) m/z: Calculated for C₁₂H₁₂N₄S: 244.08; found: 245.2(M+H)⁺.

3-(4-Phenylthiazol-2-yl)propan-1-amine

Triphenylphosphine (485 mg, 1.85 mmol) was added to a solution of2-(3-azidopropyl)-4-phenylthiazole (0.3 g, 1.23 mmol) in THF-H₂O (10 mL,8:2 v/v) at 0° C. The reaction mixture was allowed to warm up to roomtemperature, stirred for 8 h and then concentrated under reducedpressure. The residue was diluted with 1.5N HCl and the aqueous layerwas washed with CH₂Cl₂. The pH of the aqueous layer was adjusted to ˜8-9using 10% NaOH solution and the organic product was extracted withCH₂Cl₂. The combined extracts were washed with brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to afford3-(4-phenylthiazol-2-yl)propan-1-amine (240 mg, yield 89%) as a paleyellow liquid, which was carried through without further purification.MS (ESI) m/z: Calculated for C₁₂H₁₄N₂S: 218.09; found: 219.2 (M+H)⁺.

N-(3-(4-Phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from3-(4-phenylthiazol-2-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (100 mg, yield 70%). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (m,1H), 8.17-8.14 (m, 1H), 7.96-7.94 (m, 1H), 7.80-7.78 (m, 2H), 7.45-7.41(m, 1H), 7.34-7.29 (m, 4H), 3.70-3.66 (q, J=6.3 Hz, 2H), 3.27-3.23 (t,J=6.7 Hz, 2H), 2.29-2.23 (m, 2H). MS (ESI) m/z: Calculated forC₂₂H₁₇F₃N₄O₂S: 458.10; found: 459.2 (M+H)⁺.

Example 71 4-(Chloromethyl)-2-(4-fluorophenyl)oxazole

A mixture of 4-fluorobenzamide (2.5 g, 17.9 mmol) and1,3-dichloroacetone (2.7 g, 21.6 mmol) in EtOH-THF (20 mL-10 mL) washeated to 85° C. for 24 h. The reaction mixture was cooled to roomtemperature and quenched with 10% NaHCO₃ solution. The organic productwas extracted with EtOAc and the organic layer was washed with H₂O andbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 6-10% EtOAc in petroleumether) to afford 4-(chloromethyl)-2-(4-fluorophenyl)oxazole (1.2 g,yield 32%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.07-8.02 (m,2H), 7.70 (m, 1H), 7.19-7.13 (t, J=8.8 Hz, 2H), 4.58 (m, 2H). MS (ESI)m/z: Calculated for C₁₀H₇FClNO: 211.02; found: 212.0 (M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)acetonitrile

KI (3.14 g, 18.9 mmol) was added to a solution of4-(chloromethyl)-2-(4-fluorophenyl)oxazole (1.0 g, 4.7 mmol) in dry DMF(20 mL) at room temperature. The reaction mixture was stirred for 30min, diluted with EtOAc, and washed with water and brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to give crude 2-(4-fluorophenyl)-4-(iodomethyl)oxazole.The crude product was dissolved in DMF (20 mL) and sodium cyanide (0.46g, 9.4 mmol) was added to the solution. The reaction mixture was stirredat room temperature for 6 h and quenched with water. The organic productwas extracted with EtOAc and the organic layer was washed with H₂O andbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleumether) to afford 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile (0.75 g,yield 78%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.05-8.00(m, 2H), 7.73 (m, 1H), 7.20-7.14 (t, J=8.6 Hz, 2H), 3.73 (s, 2H). MS(ESI) m/z: Calculated for C₁₁H₇FN₂O: 202.05; found: 203.0 (M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)ethanamine

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile as described in example 64step 4 (120 mg, crude) and it was carried through without furtherpurification.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (55 mg, yield 46%). ¹H NMR (400 MHz, MeOD) δ 9.39(d, J=2.0 Hz, 1H), 9.19 (d, J=2.0 Hz, 1H), 8.89 (t, J=2.0 Hz, 1H),8.07-8.03 (m, 2H), 7.81 (s, 1H), 7.26-7.22 (m, 2H), 3.78-3.75 (t, J=6.9Hz, 2H), 2.97-2.94 (t, J=6.9 Hz, 2H). MS (ESI) m/z: Calculated forC₂₀H₁₃F₄N₅O₃: 447.10; found: 448.2 (M+H)⁺.

Example 72 Ethyl 2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate

Triethylamine (36 mL, 262.1 mmol) was added to a solution of2-aminoacetophenone hydrochloride (15.0 g, 87.39 mmol) in dry CH₂Cl₂(300 mL), followed by ethyl chlorooxoacetate (10 mL, 87.39 mmol) at 0°C. The reaction mixture was allowed to warm up to room temperature andstirred for 16 h. The mixture was then diluted with water and extractedwith EtOAc. The combined extracts were washed with H₂O and brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude product was purified by column chromatography (silica gel60-120 mesh, eluent 20-30% EtOAc in petroleum ether) to afford ethyl2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate (13.5 g, yield 66%). ¹H NMR(400 MHz, CDCl₃) δ 8.09 (br s, 1H), 8.02-8.00 (m, 2H), 7.68-7.64 (m,1H), 7.55-7.51 (m, 2H), 4.85-4.84 (d, J=4.9 Hz, 2H), 4.44-4.39 (q, J=7.0Hz, 2H), 1.44-1.41 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated forC₁₂H₁₃NO₄: 235.08; found: 236.2 (M+H)⁺.

Ethyl 5-phenylthiazole-2-carboxylate

P₂S₅ (25.5 g, 114.7 mmol) was added to a solution of ethyl2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate (13.5 g, 57.39 mmol) in dryCHCl₃ (150 mL), and the resulting reaction mixture was heated to refluxfor 5 h. The reaction mixture was quenched with water and the organicproduct was extracted with CHCl₃. The combined extracts were washed withH₂O and brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleumether) to afford ethyl 5-phenylthiazole-2-carboxylate (10 g, yield 75%)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.64-7.62 (m,2H), 7.48-7.39 (m, 3H), 4.53-4.47 (q, J=7.0 Hz, 2H), 1.49-1.45 (t, J=7.2Hz, 3H). MS (ESI) m/z: Calculated for C₁₂H₁₁NO₂S: 233.05; found: 234.0(M+H)⁺.

(5-Phenylthiazol-2-yl)methanol

This compound was synthesized from ethyl 5-phenylthiazole-2-carboxylateas described in example 64 step 4 (3.5 g, yield 71%) and it was carriedthrough without further purification. ¹H NMR (300 MHz, CDCl₃) δ 7.89 (s,1H), 7.57-7.54 (m, 2H), 7.44-7.35 (m, 3H), 4.97 (s, 2H). MS (ESI) m/z:Calculated for C₁₀H₉NOS: 191.04; found: 192.2 (M+H)⁺.

2-(Bromomethyl)-5-phenylthiazole

CBr₄ (8.65 g, 26.1 mmol) and Ph₃P (5.1 g, 19.6 mmol) were added to asolution of (5-phenylthiazol-2-yl)methanol (2.5 g, 13.07 mmol) in dryCH₂Cl₂ (30 mL) at 0° C. The resulting reaction mixture was stirred atroom temperature for 1 h and then concentrated under reduced pressure.The residue was diluted with diethyl ether and filtered. The clearfiltrate was removed under reduced pressure and the crude product waspurified by column chromatography (silica gel 60-120 mesh, eluent 5-10%EtOAc in petroleum ether) to afford 2-(bromomethyl)-5-phenylthiazole (2g, yield 60%). ¹H NMR (300 MHz, CDCl₃) δ 7.89 (s, 1H), 7.57-7.55 (m,2H), 7.45-7.36 (m, 3H), 4.76 (s, 2H). MS (ESI) m/z: Calculated forC₁₀H₈BrNS: 254.95; found: 256.0 (M+H)⁺.

2-(5-Phenylthiazol-2-yl)acetonitrile

NaCN (0.46 g, 9.4 mmol) was added to a solution of2-(bromomethyl)-5-phenylthiazole (2.0 g, 7.87 mmol) in dry EtOH (10 mL).The resulting reaction mixture was stirred at 70° C. for 2 h and thenconcentrated under reduced pressure, and diluted with ethyl acetate. Theorganic layer was washed with H₂O and brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel 60-120 mesh, eluent 10%EtOAc in petroleum ether) to afford 2-(5-phenylthiazol-2-yl)acetonitrile(350 mg, yield 22%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s,1H), 7.56-7.54 (m, 2H), 7.46-7.40 (m, 3H), 4.15 (s, 2H). MS (ESI) m/z:Calculated for C₁₁H₈N₂S: 200.04; found: 201.2 (M+H)⁺.

2-(5-Phenylthiazol-2-yl)ethanamine

This compound was synthesized from 2-(5-phenylthiazol-2-yl)acetonitrileas described in example 42 step 1 (100 mg, crude) and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₁₁H₁₂N₂S: 204.07; found: 205.2 (M+H)⁺.

N-(2-(5-Phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from 2-(5-phenylthiazol-2-yl)ethanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (7 mg, yield 5%). ¹H NMR (400 MHz, MeOD) δ8.60-8.59 (t, J=1.4 Hz, 1H), 8.31-8.28 (dt, J=7.8 Hz, 1.4 Hz, 1H),8.08-8.05 (dt, J=7.9 Hz, 1.3 Hz, 1H), 7.96 (s, 1H), 7.72-7.68 (t, J=7.9Hz, 1H), 7.61-7.59 (m, 2H), 7.43-7.39 (m, 2H), 7.36-7.32 (m, 1H),3.85-3.82 (t, J=6.9 Hz, 2H), 3.40-3.36 (t, J=6.8 Hz, 2H). MS (ESI) m/z:Calculated for C₂₁H₁₅F₃N₄O₂S: 444.09; found: 445.0 (M+H)⁺.

Example 73 2-(2-(4-Fluorophenyl)oxazol-4-yl)propanenitrile

NaH (360 mg, 60% dispersion in oil) was added portionwise over 5 min toa solution of 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile (1.5 g, 7.42mmol) in dry THF (60 mL) at 0° C. The resulting reaction mixture wasslowly allowed to warm up to room temperature and stirred for 1 h. Thereaction mixture was again cooled to 0° C. and a solution of methyliodide (0.5 mL, 7.4 mmol) in dry THF (10 mL) was added dropwise at 0° C.over 30 min. The reaction mixture was stirred at 0° C. for 1 h and thenat room temperature for another 1 h. The reaction mixture was quenchedwith saturated NH₄Cl solution, diluted with EtOAc and further extractedwith EtOAc. The combined extracts were washed with H₂O and brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude product was purified by column chromatography (silica 60-120 mesh,eluant 10% EtOAc in petroleum ether) to get2-(2-(4-fluorophenyl)oxazol-4-yl)propanenitrile (360 mg, yield 23%). ¹HNMR (400 MHz, CDCl₃) δ 8.05-8.02 (m, 2H), 7.71-7.70 (d, J=1.1 Hz, 1H),7.19-7.14 (t, J=8.7 Hz, 2H), 3.97-3.92 (m, 1H), 1.73-1.72 (d, J=7.2 Hz,3H). MS (ESI) m/z: Calculated for C₁₂H₁₉FN₂O: 216.07; found: 216.9(M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)propan-1-amine

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)propanenitrile as described in example1 step 3 (320 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₂H₁₃FN₂O: 220.10; found:220.8 (M+H)⁺.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (95 mg, yield 36%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.59-8.58 (t, J=1.5 Hz, 1H), 8.28-8.26 (dt, J=7.8 Hz, 1.3 Hz,1H), 8.17-8.14 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.09-8.05 (m, 2H), 7.90 (m,1H), 7.67-7.63 (t, J=7.8 Hz, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.14-7.10 (m,2H), 3.99-3.93 (ddd, J=13.2 Hz, 6.4 Hz, 4.3 Hz, 1H), 3.53-3.46 (ddd,J=13.2 Hz, 8.8 Hz, 4.3 Hz, 1H), 3.19-3.12 (m, 1H), 1.41-1.39 (d, J=7.0Hz, 3H). MS (ESI) m/z: Calculated for C₂₂H₁₆F₄N₄O₃: 460.12; found: 461.1(M+H)⁺.

Example 74 4-(Chloromethyl)-2-(3-fluorophenyl)oxazole

1,3-Dichloroacetone (3.65 g, 28.75 mmol) was added to a solution of3-fluorobenzamide (2 g, 14.37 mmol) in dry toluene (20 mL). Theresulting reaction mixture was stirred at 100° C. for 5 h. The reactionmixture was concentrated under reduced pressure and the crude productwas purified by column chromatography (silica gel 60-120 mesh, eluent10% EtOAc in petroleum ether) to afford4-(chloromethyl)-2-(3-fluorophenyl)oxazole (1.2 g, yield 39%) as ayellow liquid. ¹H NMR (300 MHz, CDCl₃) δ 7.85-7.83 (m, 1H), 7.77-7.73(m, 2H), 7.48-7.41 (m, 1H), 7.20-7.14 (m, 1H), 4.58 (d, J=0.9 Hz, 2H).

2-(2-(3-Fluorophenyl)oxazol-4-yl)acetonitrile

This compound was synthesized from4-(chloromethyl)-2-(3-fluorophenyl)oxazole as described in example 71step 2 (0.15 g, yield 35%). ¹H NMR (300 MHz, CDCl₃) δ 7.83-7.81 (m, 1H),7.76-7.70 (m, 2H), 7.49-7.42 (m, 1H), 7.22-7.15 (m, 1H), 3.74 (s, 2H).MS (ESI) m/z: Calculated for C₁₁H₇FN₂O: 202.06; found: 203.2 (M+H)⁺.

2-(2-(3-Fluorophenyl)oxazol-4-yl)ethanamine

This compound was synthesized from2-(2-(3-fluorophenyl)oxazol-4-yl)acetonitrile as described in example 42step 1 (120 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₁H₁₁FN₂O: 206.09; found:206.9 (M+H)⁺.

N-(2-(2-(3-Fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(3-fluorophenyl)oxazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (15 mg, yield 9%). ¹H NMR (400 MHz, MeOD) δ 9.39 (d,J=2.0 Hz, 1H), 9.19 (d, J=2.3 Hz, 1H), 8.90-8.88 (t, J=2.1 Hz, 1H),7.84-7.82 (m, 2H), 7.72-7.69 (m, 1H), 7.54-7.49 (m, 1H), 7.26-7.21 (m,1H), 3.79-3.76 (t, J=6.9 Hz, 2H), 2.98-2.95 (t, J=6.9 Hz, 2H). MS (ESI)m/z: Calculated for C₂₀H₁₃F₄N₅O₃: 447.10; found: 448.0 (M+H)⁺.

Example 75 Methyl 6-chloro-5-cyano-2-methylnicotinate

A mixture of methyl-5-cyano-5-hydroxy-2-methylnicotinate (2.0 g, 10.41mmol), POCl₃ (40 mL) and PCl₅ (1.08 g, 5.2 mmol) was heated to 110° C.for 24 h. The reaction mixture was concentrated under reduced pressureand quenched with ice-water. The organic product was extracted withEtOAc and the organic layer was washed with H₂O and brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by column chromatography (silica gel 60-120mesh, eluent 10-15% EtOAc in petroleum ether) to afford methyl6-chloro-5-cyano-2-methylnicotinate (1.5 g, yield 68%). ¹H NMR (300 MHz,CDCl₃) δ 8.48 (s, 1H), 3.96 (s, 3H), 2.90 (s, 3H).

Methyl 5-cyano-2-methylnicotinate

This compound was synthesized from methyl6-chloro-5-cyano-2-methylnicotinate as described in example 69 step 1(230 mg, yield 23%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.07-9.06 (d, J=2.2 Hz,1H), 8.62-8.61 (d, J=2.2 Hz, 1H), 3.87 (m, 3H), 2.78 (s, 3H). MS (ESI)m/z: Calculated for C₉H₈N₂O₂: 176.06; found: 176.7 (M+H)⁺.

5-Cyano-2-methylnicotinic acid

This compound was synthesized from methyl 5-cyano-2-methylnicotinate asdescribed in example 69 step 2 (175 mg, yield 83%) as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 13.78 (br s, 1H), 9.02-9.01 (d, J=1.8 Hz, 1H),8.56-8.55 (d, J=1.5 Hz, 1H), 2.78 (s, 3H). MS (ESI) m/z: Calculated forC₈H₆N₂O₂: 162.04; found: 160.6 (M−H)⁻.

N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-5-cyano-2-methylnicotinamide

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and5-cyano-2-methylnicotinic acid as described in example 8 step 6 (200 mg,yield 46%). ¹H NMR (300 MHz, CDCl₃) δ 8.81 (m, 1H), 8.00-7.99 (m, 1H),7.70-7.67 (m, 2H), 7.50-7.46 (m, 1H), 7.41-7.37 (m, 3H), 3.81-3.79 (d,J=5.7 Hz, 2H), 2.81 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: Calculated forC₂₁H₁₉ClN₄OS: 410.10; found: 411.1 (M+H)⁺.

5-((2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)carbamoyl)-6-methylnicotinohydrazonicacid

This compound was synthesized from methyl 5-cyano-2-methylnicotinate asdescribed in example 1 step 4 (200 mg, crude) and it was carried throughwithout further purification. ¹H NMR (400 MHz, MeOD) δ 8.71-8.70 (d,J=2.3 Hz, 1H), 8.04-8.03 (d, J=2.3 Hz, 1H), 7.93-7.91 (d, J=8.5 Hz, 2H),7.73 (s, 1H), 7.40-7.38 (d, J=8.5 Hz, 2H), 3.76 (s, 2H), 2.50 (br s,3H), 1.58 (s, 6H). MS (ESI) m/z: Calculated for C₂₁H₂₂ClN₅O₂S: 443.12;found: 444.1 (M+H)⁺.

N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from5-((2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)carbamoyl)-6-methylnicotinohydrazonicacid as described in example 1 step 5 (20 mg, yield 9%). ¹H NMR (400MHz, MeOD) δ 9.14-9.13 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H),7.93-7.91 (d, J=8.8 Hz, 2H), 7.74 (s, 1H), 7.35-7.33 (d, J=8.8 Hz, 2H),3.80 (s, 2H), 2.58 (br s, 3H), 1.60 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₃H₁₉ClF₃N₅O₂S: 521.09; found: 522.1 (M+H)⁺.

Example 76 2-Methyl-2-(5-phenyl)thiazol-2-yl)propanenitrile

This compound was synthesized from 2-(5-phenylthiazol-2-yl)acetonitrileas described in example 1 step 2 using iodomethane (200 mg, yield 58%).¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.56-7.54 (m, 2H), 7.45-7.37 (m,3H), 1.90 (s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₂N₂S: 228.07.10;found: 228.8 (M+H)⁺.

2-Methyl-2-(5-phenylthiazol-2-yl)propan-1-amine

This compound was synthesized from2-methyl-2-(5-phenylthiazol-2-yl)propanenitrile as described in example1 step 3 (70 mg, yield 34%) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₃H₁₆N₂S: 232.10; found:233.2 (M+H)⁺.

N-(2-Methyl-2-(5-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(5-phenylthiazol-2-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (20 mg, yield 17%). ¹H NMR (400 MHz, MeOD) δ 8.55 (m,1H), 8.29-8.27 (m, 1H), 8.03-8.01 (m, 1H), 7.96 (s, 1H), 7.98 (s, 1H),7.71-7.67 (t, J=7.8 Hz, 1H), 7.63-7.61 (m, 2H), 7.43-7.39 (m, 2H),7.35-7.32 (m, 1H), 3.75 (s, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₃H₁₉F₃N₄O₂S: 472.12; found: 473.1 (M+H)⁺.

Example 77 2-([1,1-Biphenyl]-3-yl)acetonitrile

NaCN (1.1 g, 22.26 mmol) was added to a solution of 3-phenylbenzylbromide (5.0 g, 20.23 mmol) in dry DMF (100 mL). The resulting reactionmixture was stirred at room temperature for 3 h and then quenched withwater. The organic product was extracted with EtOAc and the combinedextracts were washed with H₂O and brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel 60-120 mesh, eluent 5%EtOAc in petroleum ether) to afford 2-([1,1′-biphenyl]-3-yl)acetonitrile(3.8 g, yield 97%). ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.56 (m, 4H),7.50-7.45 (m, 3H), 7.42-7.36 (m, 1H), 7.34-7.31 (m, 1H), 3.83 (s, 2H).

4-([1,1-Biphenyl]-3-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from 2-([1,1′-biphenyl]-3-yl)acetonitrileas described in example 1 step 2 using 2-bromoethyl ether (0.5 g, 73%).¹H NMR (300 MHz, CDCl₃) δ 7.72-7.71 (m, 1H), 7.62-7.57 (m, 3H),7.51-7.45 (m, 4H), 7.42-7.37 (m, 1H), 4.15-4.10 (m, 2H), 3.99-3.91 (m,2H), 2.28-2.20 (m, 4H).

(4-([1,1-Biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-carbonitrile as describedin example 1 step 3 (230 mg, yield 46%) as a pale yellow oil. ¹H NMR(300 MHz, DMSO-d₆) δ 7.66-7.63 (m, 2H), 7.53-7.41 (m, 5H), 7.37-7.31 (m,2H), 3.70-3.65 (m, 2H), 3.43-3.37 (m, 2H), 2.68 (s, 2H), 2.11-2.05 (m,2H), 1.87-1.79 (m, 2H). MS (ESI) m/z: Calculated for C₁₈H₂₁NO: 267.16;found: 267.9 (M+H)⁺.

N-((4-([1,1-Biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (110 mg, yield 56%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.28 (s, 1H), 8.23-8.21 (d, J=7.7 Hz, 1H), 7.86-7.84 (d, J=8.0Hz, 1H), 7.58-7.55 (m, 6H), 7.45-7.37 (m, 4H), 5.85-5.82 (t, J=6.1 Hz,1H), 3.96-3.91 (m, 2H), 3.79-3.78 (d, J=6.4 Hz, 2H), 3.74-3.69 (m, 2H),2.27-2.22 (m, 2H), 2.10-2.04 (m, 2H). MS (ESI) m/z: Calculated forC₂₈H₂₄F₃N₃O₃: 507.18; found: 508.1 (M+H)⁺.

Example 78N-((4-([1,1′-Biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from(4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (95 mg, yield 48%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 9.40 (br s, 1H), 8.97 (br s, 1H), 8.61-8.60 (t, J=1.9 Hz,1H), 7.58-7.55 (m, 5H), 7.46-7.43 (t, J=7.5 Hz, 2H), 7.39-7.35 (m, 2H),5.89-5.86 (t, J=6.1 Hz, 1H), 3.96-3.92 (m, 2H), 3.82-3.81 (d, J=6.1 Hz,2H), 3.74-3.68 (m, 2H), 2.29-2.23 (m, 2H), 2.09-2.03 (m, 2H). MS (ESI)m/z: Calculated for C₂₇H₂₃F₃N₄O₃: 508.17; found: 507.2 (M−H)⁻.

Example 79 2-(4-Fluorophenyl)-4-(iodomethyl)oxazole

KI (3.14 g, 18.9 mmol) was added to a solution of4-chloromethyl-2-(4-fluorophenyl)-oxazole (1 g, 4.7 mmol) in dry DMF (10mL) at room temperature. The resulting reaction mixture was stirred for30 min and then diluted with EtOAc. The mixture was extracted with EtOAcand the combined extracts were washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure to get2-(4-fluorophenyl)-4-(iodomethyl)oxazole (1.2 g, crude), which wascarried through without further purification. ¹H NMR (300 MHz, CDCl₃) δ8.05-8.00 (m, 2H), 7.68 (s, 1H), 7.17-7.11 (m, 2H), 4.33 (s, 2H). MS(ESI) m/z: Calculated for C₁₀H₇FINO: 302.96; found: 304.0 (M+H)⁺.

4-(Azidomethyl)-2-(4-fluorophenyl)oxazole

A solution of 2-(4-fluorophenyl)-4-(iodomethyl)oxazole (1.2 g, 3.96mmol) in dry DMF (10 mL) was added sodium azide (515 mg, 7.9 mmol) andthe reaction mixture was heated to 70° C. for 8 h. The reaction mixturewas allowed to cool down to room temperature and diluted with EtOAc. Themixture was extracted with EtOAc and the combined extracts were washedwith water and brine, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure to afford4-(azidomethyl)-2-(4-fluorophenyl)oxazole (0.73 g, yield 85%) as a paleorange liquid, which was carried through without further purification.¹H NMR (400 MHz, CDCl₃) δ 8.04-8.01 (m, 2H), 7.67 (s, 1H), 7.16-7.12 (m,2H), 4.34 (s, 2H). MS (ESI) m/z: Calculated for C₁₀H₇FN₄O: 218.06;found: 219.2 (M+H)⁺.

(2-(4-Fluorophenyl)oxazol-4-yl)methanamine

A solution of 4-(azidomethyl)-2-(4-fluorophenyl)oxazole (0.5 g, 2.3mmol) in THF-H₂O (15 mL, 8:2 v/v) was cooled to 0° C. andtriphenylphosphine (892 mg, 3.4 mmol) was added. The reaction mixturewas allowed to warm up to room temperature and then stirred for 4 h. Thereaction mixture was concentrated under reduced pressure and the residuewas diluted with 1.5N HCl. The aqueous layer was washed with CH₂Cl₂ andthen the pH of the aqueous layer was adjusted to ˜8-9 using 10% NaOHsolution. The organic product was extracted with CH₂Cl₂ and organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to afford(2-(4-fluorophenyl)oxazol-4-yl)methanamine (330 mg, yield 75%) as a paleyellow liquid, which was carried through without further purification.¹H NMR (400 MHz, DMSO-d₆) δ 8.01-7.98 (m, 2H), 7.94 (s, 1H), 7.38-7.34(m, 2H), 3.65 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C₁₀H₉FN₂O:192.07; found: 193.2 (M+H)⁺.

N-((2-(4-Fluorophenyl)oxazol-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(2-(4-fluorophenyl)oxazol-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (65 mg, yield 26%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.35-9.32 (m, 1H), 8.60 (t, J=1.5 Hz, 1H), 8.25-8.19 (m, 2H),8.12 (m, 1H), 8.04-8.00 (m, 2H), 7.77-7.73 (t, J=7.8 Hz, 1H), 7.41-7.36(m, 2H), 4.48-4.47 (d, J=5.2 Hz, 2H). MS (ESI) m/z: Calculated forC₂₀H₁₂F₄N₄O₃: 432.08; found: 433.2 (M+H)⁺.

Example 804-(2-(4-Fluorophenyl)oxazol-4-yl)-1-methylpiperidine-4-carbonitrile

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile and2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as describedin example 16 step 1 b (430 mg, yield 30%). ¹H NMR (300 MHz, DMSO-d₆) δ8.30 (s, 1H), 8.05-8.00 (m, 2H), 7.41-7.35 (m, 2H), 2.83-2.79 (m, 2H),2.26-2.18 (m, 7H), 2.04-1.94 (m, 2H). MS (ESI) m/z: Calculated forC₁₆H₁₆FN₃O: 285.13; found: 286.2 (M+H)⁺.

(4-(2-(4-Fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methanamine

This compound was synthesized from4-(2-(4-fluorophenyl)oxazol-4-yl)-1-methylpiperidine-4-carbonitrile asdescribed in example 1 step 3 (170 mg, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₆H₂₀FN₃O:289.16; found: 290.2 (M+H)⁺.

N-((4-(2-(4-Fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(2-(4-fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (50 mg, yield 24%). ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 1H), 8.29-8.27 (m, 1H), 8.13-8.05 (m, 3H), 7.67-7.62(m, 2H), 7.17-7.13 (t, J=8.7 Hz, 2H), 3.85-3.84 (m, 2H), 3.14-3.00 (m,4H), 2.67 (m, 3H), 2.43-2.42 (m, 2H), 2.24-2.23 (m, 2H). MS (ESI) m/z:Calculated for C₂₆H₂₃F₄N₅O₃: 529.17; found: 530.2 (M+H)⁺.

Example 81 4-(Chloromethyl)-2-phenyloxazole

This compound was synthesized from 1,3-dichloroacetone and benzamide asdescribed in example 71 step 1 (65 g, yield 68%) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ 8.06-8.04 (m, 2H), 7.72 (m, 1H), 7.49-7.46 (m,3H), 4.59 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C₁₀H₈ClNO:193.03; found: 194.2 (M+H)⁺.

2-(2-Phenyloxazol-4-yl)acetonitrile

This compound was synthesized from 4-(chloromethyl)-2-phenyloxazole asdescribed in example 71 step 2 (24 g, yield 50%) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ 8.04-8.01 (m, 2H), 7.74 (t, J=1.2 Hz, 1H),7.49-7.46 (m, 3H), 3.74 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated forC₁₁H₈N₂O: 184.06; found: 185.2 (M+H)⁺.

2-Methyl-2-(2-phenyloxazol-4-yl)propanenitrile

This compound was synthesized from 2-(2-phenyloxazol-4-yl)acetonitrileusing iodomethane as described in example 1 step 2 (18 g, yield 65%) asa yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.06-8.03 (m, 2H), 7.68 (s,1H), 7.48-7.46 (m, 3H), 1.77 (s, 6H). MS (ESI) m/z: Calculated forC₁₃H₁₂N₂O: 212.09; found: 213.2 (M+H)⁺.

2-Methyl-2-(2-phenyloxazol-4-yl)propan-1-amine

This compound was synthesized from2-methyl-2-(2-phenyloxazol-4-yl)propanenitrile as described in example 1step 3 (16.2 g, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₃H₁₆N₂O: 216.13; found:217.2 (M+H)⁺.

N-(2-Methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(2-phenyloxazol-4-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (15 g, yield 44%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.66 (t, J=1.5 Hz, 1H), 8.29-8.26 (m, 2H), 8.20-8.17 (dt, J=8.0Hz, 1.2 Hz, 1H), 8.09-8.06 (m, 2H), 7.68-7.64 (t, J=7.9 Hz, 1H), 7.51(s, 1H), 7.47-7.40 (m, 3H), 3.66 (d, J=5.6 Hz, 2H), 1.43 (s, 6H). MS(ESI) m/z: Calculated for C₂₃H₁₉F₃N₄O₃: 456.14; found: 457.2 (M+H)⁺.

Example 82 2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropanenitrile

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (15 g, yield 66%) as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 8.07-8.02 (dd, J=8.9 Hz, 5.4 Hz, 2H), 7.66 (s, 1H),7.19-7.13 (t, J=8.7 Hz, 2H), 1.76 (s, 6H). MS (ESI) m/z: Calculated forC₁₃H₁₁FN₂O: 230.09; found: 231.2 (M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropanenitrile as described inexample 1 step 3 (14 g, crude) and it was carried through withoutfurther purification. ¹H NMR (300 MHz, MeOD) δ 8.07-8.03 (dd, J=8.9 Hz,5.4 Hz, 2H), 7.73 (s, 1H), 7.26-7.20 (m, 2H), 2.85 (s, 2H), 1.31 (s,6H). MS (ESI) m/z: Calculated for C₁₃H₁₅FN₂O: 234.12; found: 235.2(M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine

Sodiumtriacetoxy borohydride (197 mg, 0.9 mmol) was added to a solutionof 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (150 mg,0.62 mmol) and 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine(150 mg, 0.64 mmol) in dry DCE (2 mL) at 0° C. under nitrogen atmosphereand stirred at room temperature for 8 h (monitored by TLC, petroleumether/EtOAc 6:4). Reaction mixture was carefully quenched with 10%NaHCO₃ solution and the organic product was extracted with EtOAc. Thecombined extracts were washed with brine, dried over anhydrous Na₂SO,and concentrated under reduced pressure. The crude product was purifiedby column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc inpetroleum ether) to get2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine(50 mg, yield 18%). ¹H NMR (400 MHz, MeOD) δ 8.01 (m, 2H), 7.96-7.92 (m,3H), 7.67 (s, 1H), 7.54-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7.20-7.15 (m,1H), 3.82 (s, 2H), 2.76 (s, 2H), 1.32 (s, 6H). MS (ESI) m/z: Calculatedfor C₂₃H₂₀F₄N₄O₂: 460.15; found: 461.2 (M+H)⁺.

Example 83 4-Phenylthiazol-2(3H)-one

A suspension of 2-bromoacetophenone (5 g, 0.0251 mol), potassiumthiocyanate (8.6 g, 0.088 mol) and potassium iodide (0.25 g, 0.0015 mol)in dry DMF (25 mL) was heated to 80° C. for 2 h. The reaction mixturewas concentrated to dryness under reduced pressure and the residue wasdissolved in glacial acetic acid (25 mL) and 50% aqueous H₂SO₄ was addedto it. The reaction mixture was heated to 100° C. for 10 min. Thereaction mixture was poured in ice water and the precipitate formed wasfiltered and dried under reduced pressure to get4-phenylthiazol-2(3H)-one (3.3 g, yield 75%) as a brown solid, which wascarried through without further purification.

2-Bromo-4-phenylthiazole

A mixture of 4-phenylthiazol-2(3H)-one (300 mg, 1.7 mmol) and POBr₃(4.85 g, 17.0 mmol) was heated to 100° C. in a sealed tube for 10 h. Thereaction mixture was poured in ice water and the organic product wasextracted with EtOAc. The combined extracts were washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by column chromatography(silica 60-120 mesh, eluant 1% EtOAc in petroleum ether) to get2-bromo-4-phenylthiazole (300 mg, yield 73%) as light brown coloredliquid. ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.85 (m, 2H), 7.46-7.35 (m, 4H).MS (ESI) m/z: Calculated for C₉H₆BrNS: 240.94; found: 242.0 (M+H)⁺.

3-(4,4-Dibromobut-3-en-1-yl)benzonitrile

Tetrabutyl ammonium chloride (6.0 g, 21.83 mmol) and sodium bicarbonate(4.5 g, 54.5 mmol) were taken in dry DMF (15 mL) and cooled to 0° C. and3-iodobenzonitrile (5.0 g, 21.83 mmol) was added. Allyl alcohol (2.2 mL,32.7 mmol) was added to the reaction mixture, followed by a catalyticamount of Pd(OAc)₂ (146 mg, 0.65 mmol) and the mixture was stirred at 0°C. for 30 min. The reaction mixture was slowly warmed up to roomtemperature and further stirred for 2 h. The reaction mixture wasdiluted with water and the organic product was extracted with ether. Thecombined extracts were dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to get the crude product aldehyde. The crudealdehyde (5.0 g, 31.4 mmol) was added to a cold solution of carbontetrabromide (20.8 g, 62.8 mmol) and triphenyl phosphine (32.8 g, 125mmol) in CH₂Cl₂ (100 mL) at 0° C. The reaction mixture was furtherstirred for 2 h maintaining the same temperature. The mixture was thendiluted with hexane and the precipitate formed was filtered. The clearfiltrate was concentrated to get the crude product which was purified bycolumn chromatography (silica 60-120 mesh, eluant 10-15% EtOAc inpetroleum ether) to get 3-(4,4-dibromobut-3-en-1-yl)benzonitrile (2.25g, overall yield 33%) as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ7.66-7.63 (dt, J=7.7 Hz, 1.3 Hz, 1H), 7.55-7.49 (m, 2H), 7.44-7.42 (m,1H), 6.42-6.37 (t, J=7.2 Hz, 1H), 2.81-2.76 (m, 2H), 2.46-2.39 (q, J=7.4Hz, 2H).

3-(But-3-yn-1-yl)benzonitrile

Sodium bis(trimethylsilyl)amide (10.7 mL, 10.7 mmol, 1 M in THF) wasadded dropwise to a solution of 3-(4,4-dibromobut-3-en-1-yl)benzonitrile(2.25 g, 7.14 mmol) in dry THF (45 mL) at −60° C. The reaction mixturewas stirred for another 0.5 h maintaining the same temperature. Themixture was then cooled to −70° C. and n-BuLi (8.9 mL, 14.3 mmol, 1.6 Min hexane) was added dropwise. The reaction mixture was stirred for 0.5h, quenched with saturated NH₄Cl solution, and extracted with EtOAc. Thecombined extracts were concentrated under reduced pressure to obtain the3-(but-3-yn-1-yl)benzonitrile (600 mg, yield 54%). ¹H NMR (300 MHz,CDCl₃) δ 7.55 (m, 1H), 7.53-7.51 (m, 1H), 7.48-7.39 (m, 2H), 2.90-2.85(m, 2H), 2.54-2.48 (td, J=7.2 Hz, 2.6 Hz, 2H), 2.01-1.99 (t, J=2.6 Hz,1H).

3-(4-(4-Phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile

3-(But-3-yn-1-yl)benzonitrile (462 mg, 2.98 mmol) and2-bromo-4-phenylthiazole (650 mg, 2.71 mmol) were taken in dry DMF (20mL) and purged with nitrogen gas for 15 min. Et₃N (1.9 mL, 13.5 mmol)was added to the reaction mixture, followed by a catalytic amount ofcopper iodide (51 mg, 0.27 mmol) and Pd(PPh₃)₄ (115 mg, 0.1 mmol). Thereaction mixture was stirred at room temperature for 12 h and thenquenched with water. The organic product was extracted with EtOAc, andthe combined extracts were concentrated under reduced pressure. Thecrude product was purified by column chromatography (silica 60-120 mesh,eluant 15-20% EtOAc in petroleum ether) to get3-(4-(4-phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile (430 mg, yield50%) as a pale yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.92-7.90 (m,2H), 7.59-7.52 (m, 3H), 7.47-7.33 (m, 5H), 3.04-2.99 (m, 2H), 2.83-2.78(m, 2H). MS (ESI) m/z: Calculated for C₂₀H₁₄N₂S: 314.09; found: 315.2(M+H)⁺.

3-(4-(4-Phenylthiazol-2-yl)butyl)benzonitrile

10% Palladium on charcoal (215 mg) was added to a solution of3-(4-(4-phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile (430 mg, 1.37mmol) in ethanol (15 mL), the reaction mixture was put under ˜2 kgH₂-pressure for 48 h. The reaction mixture was filtered through a celitebed and washed thoroughly with EtOAc. The solvent was concentrated underreduced pressure to obtain 3-(4-(4-phenylthiazol-2-yl)butyl)benzonitrile(330 mg, 76%) as colorless viscous liquid. ¹H NMR (300 MHz, CDCl₃) δ7.90-7.87 (m, 2H), 7.50-7.33 (m, 8H), 3.13-3.08 (t, J=7.5 Hz, 2H),2.75-2.70 (t, J=7.5 Hz, 2H), 1.93-1.85 (m, 2H), 1.83-1.75 (m, 2H). MS(ESI) m/z: Calculated for C₂₀H₁₈N₂S: 318.12; found: 319.2 (M+H)⁺.

N′-Hydroxy-3-(4-(4-phenylthiazol-2-yl)butyl)benzimidamide

This compound was synthesized from3-(4-(4-phenylthiazol-2-yl)butyl)benzonitrile as described in example 1step 4 (290 mg, crude) and it was carried through without furtherpurification. ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H), 7.92-7.90 (m,2H), 7.51-7.39 (m, 5H), 7.33-7.18 (m, 3H), 5.74 (br s, 2H), 3.07-3.02(t, J=6.9 Hz, 2H), 2.67-2.62 (t, J=7.1 Hz, 2H), 1.80-1.67 (m, 4H). MS(ESI) m/z: Calculated for C₂₀H₂₁N₃OS: 351.14; found: 352.2 (M+H)⁺.

3-(3-(4-(4-Phenylthiazol-2-yl)butyl)phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole

This compound was synthesized fromN′-hydroxy-3-(4-(4-phenylthiazol-2-yl)butyl)benzimidamide as describedin example 1 step 5 (70 mg, yield 20%) as a yellow liquid. ¹H NMR (400MHz, CDCl₃) δ 7.96-7.95 (m, 2H), 7.90-7.88 (m, 2H), 7.47-7.40 (m, 4H),7.36-7.31 (m, 2H), 3.15-3.12 (t, J=7.5 Hz, 2H), 2.81-2.77 (t, J=7.5 Hz,2H), 1.95-1.90 (m, 2H), 1.88-1.82 (m, 2H). MS (ESI) m/z: Calculated forC₂₂H₁₈F₃N₃OS: 429.11; found: 430.2 (M+H)⁺.

Example 84 2-Diazo-1-phenylethanone

DBU (7.5 mL, 50.2 mmol) was added dropwise to a solution of2-bromo-1-phenylethanone (2.0 g, 10.05 mmol) andN,N′-bis(p-toluenesulfonyl) hydrazine (6.8 g, 20.1 mmol) in dry THF (30mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, andquenched with aqueous saturated NaHCO₃ solution. The organic product wasextracted with EtOAc and the combined extracts were washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by column chromatography(silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get2-diazo-1-phenylethanone (1.2 g, yield 82%) as a yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 7.78-7.76 (m, 2H), 7.56-7.53 (m, 1H), 7.48-7.43 (m,2H), 5.91 (s, 1H).

2-(5-Phenyloxazol-2-yl)acetonitrile

BF₃.Et₂O (1.1 mL, 8.5 mmol) was added dropwise to a solution ofmalononitrile (2.26 g, 34.2 mmol) in dry CH₂Cl₂ (20 mL) at 0° C.,followed by addition of 2-diazo-1-phenylethanone (0.5 g, 3.4 mmol) inDCM (5 mL). The reaction mixture was stirred at room temperature for 1 hand then quenched with aqueous 10% NaOH solution. The organic productwas extracted with EtOAc and the combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleumether) to get 2-(5-phenyloxazol-2-yl)acetonitrile (200 mg, yield 32%) asa brown solid. ¹H NMR (300 MHz, CDCl₃) δ 7.66-7.63 (m, 2H), 7.47-7.38(m, 3H), 7.32 (s, 1H), 4.02 (s, 2H). MS (ESI) m/z: Calculated forC₁₁H₈N₂O: 184.06; found: 185.2 (M+H)⁺.

2-Methyl-2-(5-phenyloxazol-2-yl)propanenitrile

This compound was synthesized from 2-(5-phenyloxazol-2-yl)acetonitrileusing iodomethane as described in example 1 step 2 (150 mg, yield 65%).¹H NMR (300 MHz, CDCl₃) δ 7.66-7.64 (m, 2H), 7.47-7.36 (m, 3H), 7.29 (s,1H), 1.88 (s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₂N₂O: 212.10;found: 213.2 (M+H)⁺.

2-Methyl-2-(5-phenyloxazol-2-yl)propan-1-amine

This compound was synthesized from2-methyl-2-(5-phenyloxazol-2-yl)propanenitrile as described in example 1step 3 (100 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₃H₁₆N₂O: 216.13; found:217.2 (M+H)⁺.

N-(2-Methyl-2-(5-phenyloxazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(5-phenyloxazol-2-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (18 mg, yield 10%) as a yellow viscous liquid. ¹H NMR(400 MHz, MeOD) δ 8.50-8.49 (t, J=1.8 Hz, 1H), 8.28-8.25 (dt, J=7.8 Hz,1.4 Hz, 1H), 8.00-7.98 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.68-7.64 (m, 3H),7.39-7.36 (m, 3H), 7.32-7.27 (m, 1H), 4.58 (s, 2H), 1.54 (s, 6H). MS(ESI) m/z: Calculated for C₂₃H₁₉F₃N₄O₃: 456.14; found: 457.2 (M+H)⁺.

Example 85 Ethyl 2-phenylthiazole-5-carboxylate

Ethyl-3-ethoxyacrylate (4.0 g, 27.7 mmol) was dissolved in dioxane-H₂O(30 ml, 1:1 v/v) and cooled to −10° C. N-Bromosuccinimide (5.43 g, 30.5mmol) was added to this solution and the reaction mixture was allowed towarm up to room temperature and further stirred for 1 h. Thiobenzamide(3.8 g, 27.7 mmol) was then added and the reaction mixture was furtherheated to 80° C. for 1 h. The reaction mixture was then cooled to roomtemperature and quenched with aqueous ammonia solution. The organicproduct was extracted with EtOAc and combined extracts were washed withH₂O and brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 5-10% EtOAc in petroleumether) to afford ethyl 2-phenylthiazole-5-carboxylate (1.1 g, yield 17%)as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.43 (s, 1H), 8.01-7.98 (m,2H), 7.48-7.48 (m, 3H), 4.44-4.37 (q, J=7.2 Hz, 2H), 1.44-1.39 (t, J=7.2Hz, 3H). MS (ESI) m/z: Calculated for C₁₂H₁₁NO₂S: 233.05; found: 234.0(M+H)⁺.

(2-Phenylthiazol-5-yl)methanol

This compound was synthesized from ethyl 2-phenylthiazole-5-carboxylateas described in example 1 step 3 (390 mg, yield 95%) as a yellow solid.¹H NMR (300 MHz, CDCl₃) δ 7.95-7.92 (m, 2H), 7.71 (s, 1H), 7.46-7.43 (m,3H), 4.91 (s, 2H). MS (ESI) m/z: Calculated for C₁₀H₉NOS: 191.04; found:192.2 (M+H)⁺.

5-(Bromomethyl)-2-phenylthiazole

(2-phenylthiazol-5-yl)methanol (390 mg, 2.03 mmol) was dissolved in dryCH₂Cl₂ (10 mL) and cooled to 0° C. Triphenyl phosphine (800 mg, 3.05mmol) was then added, followed by carbon tetrabromide (1.35 g, 4.07mmol). The reaction mixture was allowed to warm up to room temperatureand stirred for 1 h. The reaction mixture was then concentrated underreduced pressure and the crude product was purified by columnchromatography (silica 60-120 mesh, eluant 5% EtOAc in petroleum ether)to get 5-(bromomethyl)-2-phenylthiazole (250 mg, yield 48%) as lightyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.92 (m, 2H), 7.80 (s, 1H),7.46-7.45 (m, 3H), 4.77 (s, 2H). MS (ESI) m/z: Calculated for C₁₀H₈BrNS:254.95; found: 256.0 (M+H)⁺.

2-(2-Phenylthiazol-5-yl)acetonitrile

KCN (154 mg, 2.36 mmol) was added to a solution of5-(bromomethyl)-2-phenylthiazole (400 mg, 1.57 mmol) in dry DMF (10 mL).The resulting reaction mixture was stirred at room temperature for 10 h.The mixture was then quenched with water and the organic product wasextracted with EtOAc. The combined extracts were washed with H₂O andbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 20% EtOAc in petroleumether) to afford 2-(2-phenylthiazol-5-yl)acetonitrile (230 mg, yield73%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.94-7.90 (m, 2H), 7.76(s, 1H), 7.47-7.45 (m, 3H), 3.98 (d, J=1.1 Hz, 2H). MS (ESI) m/z:Calculated for C₁₁H₈N₂S: 200.05; found: 201.2 (M+H)⁺.

2-(2-Phenylthiazol-5-yl)ethanamine

This compound was synthesized from 2-(2-phenylthiazol-5-yl)acetonitrileas described in example 42 step 1 (150 mg, crude) and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₁₁H₁₂N₂S: 204.08; found: 205.2 (M+H)⁺.

N-(2-(2-Phenylthiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from 2-(2-phenylthiazol-5-yl)ethanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (35 mg, yield 27%) as an off white solid.¹H NMR (400 MHz, MeOD) δ 8.61 (t, J=1.5 Hz, 1H), 8.32-8.29 (dt, J=7.8Hz, 1.3 Hz, 1H), 8.09-8.06 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.90-7.88 (m,2H), 7.73-7.69 (t, J=7.9 Hz, 1H), 7.66 (s, 1H), 7.47-7.45 (m, 3H),3.75-3.71 (t, J=6.8 Hz, 2H), 3.28-3.25 (t, J=6.8 Hz, 2H). MS (ESI) m/z:Calculated for C₂₁H₁₅F₃N₄O₂S: 444.09; found: 445.0 (M+H)⁺.

Example 86 2-Methyl-2-(2-phenylthiazol-5-yl)propanenitrile

This compound was synthesized from 2-(2-phenylthiazol-5-yl)acetonitrileusing iodomethane as described in example 1 step 2 (210 mg, yield 80%)as a yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.90 (m, 2H), 7.79(s, 1H), 7.47-7.45 (m, 3H), 1.86 (s, 6H). MS (ESI) m/z: Calculated forC₁₃H₁₂N₂S: 228.07; found: 229.2 (M+H)⁺.

2-Methyl-2-(2-phenylthiazol-5-yl)propan-1-amine

This compound was synthesized from2-methyl-2-(2-phenylthiazol-5-yl)propanenitrile as described in example1 step 3 (100 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₃H₁₆N₂S: 232.10; found:233.2 (M+H)⁺.

N-(2-Methyl-2-(2-phenylthiazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(2-phenylthiazol-5-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (70 mg, yield 51%). ¹H NMR (400 MHz, MeOD) δ 8.55 (t,J=1.6 Hz, 1H), 8.29-8.26 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.03-8.01 (dt,J=7.8 Hz, 1.5 Hz, 1H), 7.91-7.88 (m, 2H), 7.70-7.66 (m, 2H), 7.47-7.45(m, 3H), 3.64 (s, 2H), 1.53 (s, 6H). MS (ESI) m/z: Calculated forC₂₃H₁₉F₃N₄O₂S: 472.12; found: 473.2 (M+H)⁺.

Example 87N-((4-(2-(4-Chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (50 mg, yield 23%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.54-8.51 (m, 1H), 8.39 (m, 1H), 8.18-8.16 (d, J=7.6 Hz, 1H),8.04-8.02 (d, J=7.6 Hz, 1H), 7.91-7.89 (d, J=8.2 Hz, 2H), 7.69-7.65 (t,J=7.8 Hz, 1H), 7.52-7.49 (m, 3H), 3.49-3.48 (m, 2H), 2.66-2.63 (m, 2H),2.31-2.28 (m, 2H), 2.12-2.04 (m, 5H), 1.90-1.84 (m, 2H). MS (ESI) m/z:Calculated for C₂₆H₂₃ClF₃N₆O₂S: 561.12; found: 562.0 (M+H)⁺.

Example 88 1-(5-Bromothiophen-2-yl)-2,2,2-trifluoroethanol

CsF (400 mg, 2.6 mmol) was added to a solution of5-bromothiophene-2-carbaldehyde (5.0 g, 26.17 mmol) in dry1,2-dimethoxyethane (20 mL), followed by trifluoromethyl trimethylsilane(4.6 mL, 31.4 mmol) dropwise at 0° C. The reaction mixture was stirredat room temperature for 3 h, quenched with 1.5N HCl, and stirred for anadditional 30 min. The crude product was extracted with CH₂Cl₂. Thecombined extracts were dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure. The crude product was purified by columnchromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleumether) to get 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanol (4 g,yield 59%). ¹H NMR (400 MHz, CDCl₃) δ 7.01 (m, 1H), 6.95 (m, 1H),5.23-5.18 (q, J=5.9 Hz, 1H), 3.07 (br s, 1H). MS (ESI) m/z: Calculatedfor C₆H₄BrF₃OS: 261.91; found: 260.7 (M−1)⁻.

1-(5-Bromothiophen-2-yl)-2,2,2-trifluoroethanone

This compound was synthesized from1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanol as described in example47 step 2 (0.8 g, yield 42%). ¹H NMR (400 MHz, CDCl₃) δ 7.72-7.71 (m,1H), 7.24-7.23 (d, J=4.3 Hz, 1H).

3-(5-(2,2,2-Trifluoroacetyl)thiophen-2-yl)benzoic acid

1-(5-Bromothiophen-2-yl)-2,2,2-trifluoroethanone (0.8 g, 3.09 mmol) and3-carboxyphenylboronic acid (0.5 g, 3.01 mmol) were dissolved in DMF (10mL) and the solution was purged with argon for 10 min. 2M aqueoussolution of Na₂CO₃ (0.65 g, 6.17 mmol) and catalytic Pd(PPh₃)₄ (178 mg,0.15 mmol) were added to the reaction mixture and heated to 90° C. for10 h. The reaction mixture was cooled to room temperature, diluted withwater and acidified to pH ˜6 with 1.5 N HCl. The crude product wasextracted with EtOAc. The combined extracts were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product wastriturated with diethyl ether to get3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid (700 mg, yield79%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (br s, 1H), 8.31-8.30 (m, 1H),8.16-8.11 (m, 2H), 8.04-8.02 (d, J=7.6 Hz, 1H), 7.93-7.92 (d, J=4.3 Hz,1H), 7.67-7.63 (t, J=7.8 Hz, 1H). MS (ESI) m/z: Calculated forC₁₃H₇F₃O₃S: 300.01; found: 299.0 (M−1)⁻.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described inexample 8 step 6 (8 mg, yield 5%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.53-8.50(t, J=6.2 Hz, 1H), 8.21 (m, 1H), 8.17-8.16 (m, 1H), 8.03-7.98 (m, 4H),7.93-7.91 (m, 1H), 7.88-7.87 (d, J=4.3 Hz, 1H), 7.63-7.59 (t, J=7.8 Hz,1H), 7.34-7.30 (t, J=8.8 Hz, 2H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s,6H).

Example 89 5-(5-(2,2,2-Trifluoroacetyl)thiophen-2-yl)nicotinic acid

This compound was synthesized from1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanone and 5-borononicotinicacid as described in example 88 step 3 (470 mg, yield 82%). ¹H NMR (300MHz, DMSO-d₆) δ 13.74 (br s, 1H), 9.30-9.29 (s, 1H), 9.11-9.10 (m, 1H),8.59-8.58 (t, J=2.0 Hz, 1H), 8.20-8.19 (m, 1H), 8.07-8.05 (m, 1H).

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinic acid as described inexample 8 step 6 (45 mg, yield 26%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.21(d, J=2.1 Hz, 1H), 9.01 (s, 1H), 8.66-8.60 (m, 1H), 8.52-8.51 (t, J=2.0Hz, 1H), 8.21-8.20 (m, 1H), 8.02-7.98 (m, 4H), 7.36-7.30 (m, 2H),3.53-3.52 (d, J=6.1 Hz, 2H), 1.30 (s, 6H).

Example 90N-((4-(2-(4-Chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide

This compound was synthesized from(4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamineand 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as describedin example 8 step 6 (8.5 mg, yield 4%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.54(m, 1H), 8.14-8.13 (m, 2H), 8.00-7.86 (m, 4H), 7.82-7.77 (m, 1H), 7.70(m, 1H), 7.60-7.56 (m, 1H), 7.48-7.46 (m, 2H), 3.50 (m, 2H), 3.39-3.17(m, 4H), 2.57 (m, 3H), 2.43 (m, 2H), 2.08 (m, 2H).

Example 91 5-Cyano-2-fluorobenzoic acid

NaH₂PO₄ (87 mg, 0.724 mmol) in water (3.5 mL) was added to a solution of5-cyano-2-fluorobenzaldehyde (500 mg, 3.35 mmol) in acetonitrile (7 mL),followed by 30% H₂O₂ (0.31 mL). Sodium chlorite (434 mg, 4.8 mmol) inwater (3.5 mL) was added dropwise to this reaction mixture at 0° C. Themixture was stirred at room temperature for 1 h, quenched with aqueoussodium sulfite solution at 0° C. and then acidified with 1.5N HClsolution. The aqueous solution was extracted with EtOAc and the combinedextracts were dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to afford 5-cyano-2-fluorobenzoic acid (500 mg,yield 90%). ¹H NMR (300 MHz, DMSO-d₆) δ 13.79 (br s, 1H), 8.30-8.27 (dd,J=6.6 Hz, 2.2 Hz, 1H), 8.17-8.12 (ddd, J=8.6 Hz, 4.4 Hz, 2.3 Hz, 1H),7.60-7.53 (dd, J=10.5 Hz, 8.8 Hz, 1H). MS (ESI) m/z: Calculated forC₈H₄FNO₂: 165.02; found: 163.6 (M−H)⁻.

2-Fluoro-5-(N′-hydroxycarbamimidoyl)benzoic acid

This compound was synthesized from 5-cyano-2-fluorobenzoic acid asdescribed in example 1 step 4 (400 mg, crude) and it was carried throughwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 13.72 (br s,1H), 11.43 (br s, 1H), 10.39 (br s, 2H), 8.24-8.22 (m, 1H), 8.04-8.01(m, 1H), 7.61-7.56 (t, J=9.6 Hz, 1H). MS (ESI) m/z: Calculated forC₈H₇FN₂O₃: 198.04; found: 198.8 (M+H)⁺.

2-Fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

This compound was synthesized from 2-fluoro-5-(N′hydroxycarbamimidoyl)benzoic acid as described in example 1 step 5 (130mg, yield 23%). ¹H NMR (300 MHz, DMSO-d₆) δ 13.72 (br s, 1H), 8.51-8.48(dd, J=6.9 Hz, 2.3 Hz, 1H), 8.33-8.29 (m, 1H), 7.62-7.55 (dd, J=10.2 Hz,8.9 Hz, 1H). MS (ESI) m/z: Calculated for C₁₀H₄F₄N₂O₃: 276.02; found:274.8 (M−H)⁻.

2-Fluoro-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and2-fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (75 mg, yield 32%) as a yellow viscousliquid. ¹H NMR (400 MHz, MeOD) δ 8.46-8.43 (dd, J=6.8 Hz, 2.3 Hz, 1H),8.29-8.25 (ddd, J=8.7 Hz, 4.8 Hz, 2.4 Hz, 1H), 8.09-8.05 (dd, J=9.0 Hz,5.3 Hz, 2H), 7.77 (s, 1H), 7.47-7.42 (dd, J=10.3 Hz, 8.8 Hz, 1H),7.25-7.20 (t, J=8.9 Hz, 2H), 3.67 (s, 2H), 1.41 (s, 6H). MS (ESI) m/z:Calculated for C₂₃H₁₇F₃N₄O₃: 492.12; found: 493.2 (M+H)⁺.

Example 92 (E)-ethyl 2-styryloxazole-4-carboxylate

Ethyl bromopyruvate (10 mL, 81.55 mmol) was added dropwise to a solutionof 3-phenylacrylamide (5 g, 33.97 mmol) and NaHCO₃ (11.42 g, 135.89mmol) in anhydrous THF (120 mL) at 0° C. The reaction mixture was heatedto reflux for 23 h. The mixture was then filtered through Celite and thesolvent was removed under reduced pressure. The crude product wasdissolved in anhydrous THF (80 mL) and trifluoroacetic anhydride (37 mL)was added dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 10 h, and quenched with saturated NaHCO₃ solution at 0°C. The organic product was extracted with EtOAc, and the combinedextracts were washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel 60-120 mesh, eluent 10% EtOAc inpetroleum ether) to afford (E)-ethyl 2-styryloxazole-4-carboxylate (4.22g, yield 51%) as an off white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.21 (s,1H), 7.66-7.61 (d, J=16.4 Hz, 1H), 7.56-7.52 (m, 2H), 7.44-7.36 (m, 3H),7.00-6.94 (d, J=16.4 Hz, 1H), 4.46-4.39 (q, J=7.0 Hz, 2H), 1.44-1.39 (t,J=7.0 Hz, 3H). MS (ESI) m/z: Calculated for C₁₄H₁₃NO₃: 243.09; found:243.8 (M+H)⁺.

Ethyl 2-formyloxazole-4-carboxylate

OsO₄ [10 mL, 0.41 mmol, 4% in H₂O] was added dropwise to a solution of(E)-ethyl 2-styryloxazole-4-carboxylate (4 g, 16.44 mmol) andtrimethylamine N-oxide (1.84 g, 24.5 mmol) in acetone-H₂O (88 mL; 10:1v/v). The reaction mixture was stirred at room temperature for 3 h andthen concentrated under reduced pressure. The crude product was purifiedby column chromatography (silica gel 60-120 mesh, eluent 50% EtOAc inpetroleum ether) to afford an intermediate (1.5 g, 5.41 mmol) which wasdissolve in anhydrous benzene (30 mL). K₂CO₃ (0.85 g, 6.17 mmol) wasadded to the reaction mixture followed by Pb(OAc)₄ (2.73 g, 6.17 mmol).The reaction mixture was stirred at room temperature for 20 min and thenquenched with saturated NaHCO₃ solution. The organic product wasextracted with EtOAc. Solvent was removed under reduced pressure and thecrude product was purified by column chromatography (silica gel 60-120mesh, eluent 30% EtOAc in petroleum ether) to afford ethyl2-formyloxazole-4-carboxylate (0.65 g, overall yield 24%) as an offwhite solid. ¹H NMR (400 MHz, CDCl₃) δ 9.84 (s, 1H), 8.43 (s, 1H),4.49-4.44 (q, J=7.0 Hz, 2H), 1.45-1.41 (t, J=7.0 Hz, 3H). MS (ESI) m/z:Calculated for C₇H₇NO₄: 169.04; found: 169.8 (M+H)⁺.

Ethyl 2-cyanooxazole-4-carboxylate

A solution of ethyl 2-formyloxazole-4-carboxylate (650 mg, 3.84 mmol) inmethanol (25 mL) was cooled to 0° C. and 50% aqueous hydroxylamine (0.22mL, 7.68 mmol) was added dropwise. The reaction mixture was stirred atroom temperature for 3 h. Solvent was removed under reduced pressure andthe crude product (0.52 g) obtained was dissolved in DMF (20 mL). T₃P(3.4 mL, 5.65 mmol; 50% in EtOAc) was added to the reaction mixture andheated to 100° C. for 2 h. The reaction mixture was quenched withsaturated NaHCO₃ solution and the organic product was extracted withEtOAc. Solvent was removed under reduced pressure and the crude productwas purified by column chromatography (silica gel 60-120 mesh, eluent10% EtOAc in petroleum ether) to afford ethyl2-cyanooxazole-4-carboxylate (0.34 g, yield 53%) as an off white solid.¹H NMR (300 MHz, CDCl₃) δ 8.39 (s, 1H), 4.48-4.41 (q, J=7.0 Hz, 2H),1.44-1.39 (t, J=7.0 Hz, 3H).

Ethyl 2-(N′-hydroxycarbamimidoyl)oxazole-4-carboxylate

This compound was synthesized from ethyl 2-cyanooxazole-4-carboxylate asdescribed in example 1 step 4 (500 mg, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₇H₉N₃O₄:199.06; found: 199.8 (M+H)⁺.

Ethyl 2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxylate

This compound was synthesized from ethyl2-(N′-hydroxycarbamimidoyl)oxazole-4-carboxylate as described in example1 step 5 (50 mg, yield 7%). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H),4.49-4.44 (q, J=7.0 Hz, 2H), 1.45-1.41 (t, J=7.0 Hz, 3H). MS (ESI) m/z:Calculated for C₉H₆F₃N₃O₄: 277.03; found: 277.9 (M+H)⁺.

2-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxylic acid

This compound was synthesized from ethyl2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxylate asdescribed in example 43 step 2 (25 mg, 56%) as an off white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 13.65 (br s, 1H), 9.18 (s, 1H). MS (ESI) m/z:Calculated for C₇H₂F₃N₃O₄: 249.00; found: 248.0 (M−H)⁻.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxylic acid asdescribed in example 8 step 6 (6 mg, yield 13%). ¹H NMR (400 MHz, CDCl₃)δ 8.88-8.86 (m, 1H), 8.49 (s, 1H), 8.25-8.21 (m, 2H), 7.46 (s, 1H),7.23-7.19 (t, J=8.8 Hz, 2H), 3.62-3.60 (d, J=6.0 Hz, 2H), 1.39 (s, 6H).MS (ESI) m/z: Calculated for C₂₀H₁₅F₄N₅O₄: 465.11; found: 466.1 (M+H)⁺.

Example 93 Methyl 1-methyl-2-phenyl-1H-imidazole-5-carboxylate

Methyl-2-bromo-1-methyl-1H-imidazole-5-carboxylate (1 g, 4.56 mmol) andphenylboronic acid (0.67 g, 5.48 mmol) were dissolved in toluene-EtOH(80 mL, 5:3 v/v) and the solution was purged with argon for 10 min.K₂CO₃ (10 mL, 2M solution) and catalytic PdCl₂(dppf) (82 mg, 0.12 mmol)were added and the reaction mixture was heated to 100° C. for 1 h. Thereaction mixture was then cooled to room temperature and concentratedunder reduced pressure. The residue was diluted with water and washedwith EtOAc. The aqueous layer was acidified to pH ˜6 using 1.5N HCl andthe crude product was extracted with EtOAc. The combined extracts weredried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude product was purified by column chromatography (silica 60-120mesh, eluent 35-45% EtOAc in petroleum ether) to get methyl1-methyl-2-phenyl-1H-imidazole-5-carboxylate (800 mg, yield 81%) as apale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.63-7.61 (m,2H), 7.51-7.48 (m, 3H), 3.96 (s, 3H), 3.89 (s, 3H). MS (ESI) m/z:Calculated for C₁₂H₁₂N₂O₂: 216.09; found: 2168.8 (M+H)⁺.

(1-Methyl-2-phenyl-1H-imidazol-5-yl)methanol

This compound was synthesized from1-methyl-2-phenyl-1H-imidazole-5-carboxylate as described in example 1step 3 (600 mg, yield 86%) as a white solid. ¹H NMR (300 MHz, MeOD) δ7.60-7.57 (m, 2H), 7.50-7.48 (m, 3H), 7.00 (s, 1H), 4.64 (s, 2H), 3.72(s, 3H). MS (ESI) m/z: Calculated for C₁₁H₁₂N₂O: 188.09; found: 188.8(M+H)⁺.

5-(Chloromethyl)-1-methyl-2-phenyl-1H-imidazole hydrochloride

A solution of (1-methyl-2-phenyl-1H-imidazol-5-yl)methanol (0.600 g,3.19 mmol) in dry SOCl₂ (11 mL) was refluxed at 80° C. for 1 h. Thereaction mixture was concentrated under reduced pressure and the residuewas co-evaporated with CH₂Cl₂, and then triturated with diethyl ether,filtered and dried under suction to afford5-(chloromethyl)-1-methyl-2-phenyl-1H-imidazole hydrochloride (0.67 g,yield 86%) as a white solid. ¹H NMR (300 MHz, MeOD) δ 7.79-7.79 (m, 6H),4.98 (s, 2H), 3.93 (s, 3H).

2-(1-Methyl-2-phenyl-1H-imidazol-5-yl)acetonitrile

This compound was synthesized from5-(chloromethyl)-1-methyl-2-phenyl-1H-imidazole hydrochloride asdescribed in example 77 step 1 (400 mg, yield 90%). ¹H NMR (300 MHz,CDCl₃) δ 7.61-7.58 (m, 2H), 7.49-7.44 (m, 3H), 7.12 (s, 1H), 3.79 (s,2H), 3.71 (s, 3H). MS (ESI) m/z: Calculated for C₁₂H₁₁N₃: 197.10; found:197.9 (M+H)⁺.

2-(1-Methyl-2-phenyl-1H-imidazol-5-yl)propanenitrile

This compound was synthesized from2-(1-methyl-2-phenyl-1H-imidazol-5-yl)acetonitrile as described inexample 1 step 2 (170 mg, yield 53%) as colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.61-7.58 (m, 2H), 7.52-7.46 (m, 3H), 7.10 (m, 1H), 4.00-3.95(q, J=7.2 Hz, 1H), 3.74 (s, 3H), 1.83-1.81 (d, J=7.2 Hz, 3H). MS (ESI)m/z: Calculated for C₁₃H₁₃N₃: 211.11; found: 211.9 (M+H)⁺.

2-(1-Methyl-2-phenyl-1H-imidazol-5-yl)propan-1-amine

This compound was synthesized from2-(1-methyl-2-phenyl-1H-imidazol-5-yl)propanenitrile as described inexample 1 step 3 (155 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₃H₁₇N₃: 215.14;found: 215.9 (M+H)⁺.

N-(2-(1-Methyl-2-phenyl-1H-imidazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(1-methyl-2-phenyl-1H-imidazol-5-yl)propan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (35 mg, yield 28%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.36(d, J=2.1 Hz, 1H), 9.28-9.26 (m, 2H), 8.84-8.83 (t, J=2.0 Hz, 1H),7.65-7.63 (m, 2H), 7.50-7.42 (m, 4H), 6.92 (s, 1H), 3.70 (s, 3H),3.66-3.61 (m, 1H), 3.32-3.28 (m, 1H), 3.22-3.17 (m, 1H), 1.33-1.32 (d,J=6.7 Hz, 3H). MS (ESI) m/z: Calculated for C₂₂H₁₉F₃N₆O₂: 456.15; found:457.2 (M+H)⁺.

Example 94 Methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate

N,N-Diisopropylethylamine (11 mL, 63.3 mmol) was added dropwise to asolution of methyl 4-fluorobenzimidate hydrochloride (10 g, 52.74 mmol)and DL-serine methyl ester HCl salt (9.9 g, 63.63 mmol) in dry CH₂Cl₂(200 mL) at 0° C. The reaction mixture was stirred at room temperaturefor 24 h and then concentrated under reduced pressure. The reactionmixture was diluted with CH₂Cl₂ and the organic layer was washed withH₂O and brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to get methyl2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.5 g, yield 81%)as an orange liquid. ¹H NMR (300 MHz, CDCl₃) δ 8.02-7.97 (m, 2H),7.13-7.07 (t, J=8.7 Hz, 2H), 4.98-4.92 (m, 1H), 4.73-4.57 (m, 2H), 3.83(s, 3H). MS (ESI) m/z: Calculated for C₁₁H₁₀FNO₃: 223.06; found: 223.8(M+H)⁺.

Methyl 2-(4-fluorophenyl)oxazole-4-carboxylate

Benzoyl peroxide (0.49 g, 2.0 mmol) was added to a solution of methyl2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.0 g, 40.3 mmol)in dry benzene (180 mL) and the mixture was refluxed for 15 min.N-bromosuccinimide (8.6 g, 48.3 mmol) was then added and the reactionmixture was refluxed for 2 h. The reaction mixture was quenched withice-cold water and the crude product was extracted with EtOAc. Thecombined extracts were washed with 10% aqueous NaHCO₃ solution, H₂O andbrine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude product was purified by column chromatography(silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to getmethyl 2-(4-fluorophenyl)oxazole-4-carboxylate (6 g, yield 67%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 8.14-8.10 (m, 2H),7.19-7.15 (t, J=8.5 Hz, 2H), 3.96 (s, 3H). MS (ESI) m/z: Calculated forC₁₁H₈FNO₃: 221.05; found: 221.8 (M+H)⁺.

(2-(4-Fluorophenyl)oxazol-4-yl)methanol

This compound was synthesized from methyl2-(4-fluorophenyl)oxazole-4-carboxylate as described in example 64 step4 (4.5 g, yield 86%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ8.06-8.01 (m, 2H), 7.65 (s, 1H), 7.18-7.12 (t, J=8.7 Hz, 2H), 4.68 (s,2H). MS (ESI) m/z: Calculated for C₁₀H₈FNO₂: 193.05; found: 193.8(M+H)⁺.

2-(4-Fluorophenyl)oxazole-4-carbaldehyde

This compound was synthesized from(2-(4-fluorophenyl)oxazol-4-yl)methanol as described in example 47 step2 (2.8 g, yield 63%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 10.01(s, 1H), 8.32 (s, 1H), 8.14-8.10 (m, 2H), 7.23-7.17 (t, J=8.8 Hz, 2H).MS (ESI) m/z: Calculated for C₁₀H₆FNO₂: 191.04; found: 191.8 (M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile

KH₂PO₄ (712 mg, 5.23 mmol) and NaCN (251 mg, 5.12 mmol) were added to asolution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (500 mg, 2.62 mmol)in DMF-H₂O (10 mL, 4:6, v/v). The resulting reaction mixture was stirredat room temperature for 1 h, then diluted with water and extracted withEtOAc. The combined extracts were washed with H₂O and brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to afford2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile (500 mg, yield87%). ¹H NMR (400 MHz, CDCl₃) δ 8.07-8.02 (m, 2H), 7.88 (s, 1H),7.20-7.16 (t, J=8.8 Hz, 2H), 5.62 (s, 1H), 4.38 (br s, 1H). MS (ESI)m/z: Calculated for C₁₁H₇FN₂O₂: 218.05; found: 218.8 (M+H)⁺.

2-Amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol

Trifluoroacetic acid (0.35 mL, 4.60 mmol) was added dropwise to asuspension of NaBH₄ (0 174 g, 4.60 mmol) in dry THF (10 mL) at 0° C.,followed by addition of2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile (0 20 g, 0.92mmol) also portionwise. The reaction mixture was stirred at roomtemperature for 8 h, and then concentrated under reduced pressure anddiluted with ice-water. The mixture was acidified to pH ˜2 using 1.5NHCl at 0° C. and then heated to 50° C. for 20 min. The solution wasbasified with aqueous NH₄OH solution and the organic product wasextracted with CHCl₃. The combined extracts were washed with brine andconcentrated under reduced pressure to afford2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol (120 mg, crude), whichwas carried through without further purification. MS (ESI) m/z:Calculated for C₁₁H₁₁FN₂O₂: 222.08; found: 222.8 (M+H)⁺.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (70 mg, yield 39%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (m,1H), 8.28-8.26 (m, 1H), 8.08-8.01 (m, 3H), 7.73 (s, 1H), 7.66-7.62 (m,1H), 7.17-7.08 (m, 3H), 5.05-5.03 (m, 1H), 4.12-4.06 (ddd, J=14.1 Hz,6.3 Hz, 3.8 Hz, 1H), 3.91-3.85 (m, 1H), 3.77 (br s, 1H). MS (ESI) m/z:Calculated for C₂₁H₁₄F₄N₄O₄: 462.10; found: 463.1 (M+H)⁺.

Example 95 5-(5-(Difluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid

This compound was synthesized from 5-(N′-hydroxycarbamimidoyl)nicotinicacid using ethyl difluoroacetate as described in example 1 step 5 (100mg, yield 30%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.94 (br s, 1H), 9.40 (d,J=2.1 Hz, 1H), 9.28 (d, J=2.1 Hz, 1H), 8.76-8.75 (t, J=2.1 Hz, 1H),7.73-7.47 (m, 1H). MS (ESI) m/z: Calculated for C₉H₅F₂N₃O₃: 241.03;found: 241.8 (M+H)⁺.

5-(5-(Difluoromethyl)-1,2,4-oxadiazol-3-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)nicotinamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (45 mg, yield 24%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.32(d, J=2.1 Hz, 1H), 9.20 (d, J=2.1 Hz, 1H), 8.82-8.78 (m, 1H), 8.75-8.74(t, J=2.1 Hz, 1H), 8.04-8.00 (m, 3H), 7.74-7.48 (m, 1H), 7.38-7.33 (t,J=8.9 Hz, 2H), 3.55-3.53 (d, J=6.1 Hz, 2H), 1.31 (s, 6H). MS (ESI) m/z:Calculated for C₂₂H₁₈F₃N₆O₃: 457.14; found: 458.2 (M+H)⁺.

Example 962-(Dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile

2-(4-Fluorophenyl)oxazole-4-carbaldehyde (1.0 g, 5.23 mmol) wasdissolved in THF-MeOH (20 mL, 1:1 v/v). This solution was added to asolution of dimethylamine hydrochloride (470 mg, 5.7 mmol) and NaCN (640mg, 13.0 mmol) in water. The resulting reaction mixture was stirred atroom temperature for 2 h, and then diluted with water and extracted withEtOAc. The combined extracts were washed with H₂O and brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to afford2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile (1.0 g,crude) as a brown oil, which was used without further purification. MS(ESI) m/z: Calculated for C₁₃H₁₂FN₃O: 245.10; found: 245.9 (M+H)⁺.

1-(2-(4-Fluorophenyl)oxazol-4-yl)-N1,N1-dimethylethane-1,2-diamine

This compound was synthesized from2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile asdescribed in example 1 step 3 (0.6 g) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₃H₁₆FN₃O: 249.13;found: 249.9 (M+H)⁺.

N-(2-(Dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamidehydrochloride

N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamidewas synthesized from1-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylethane-1,2-diamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6. The free base was then stirred with HCl in dioxanesolution (4 mL) for 0.5 h at 0° C. to room temperature. The reactionmixture was concentrated and triturated with diethyl ether to affordN-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamidehydrochloride (130 mg, yield 16%) as light brown solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.39 (br s, 1H), 9.18-9.15 (t, J=5.6 Hz, 1H), 8.55-8.54 (m,2H), 8.27-8.25 (m, 1H), 8.21-8.19 (m, 1H), 8.11-8.07 (m, 2H), 7.79-7.75(t, J=7.8 Hz, 1H), 7.45-7.41 (t, J=8.9 Hz, 2H), 4.84-4.81 (t, J=6.1 Hz,1H), 4.20-4.13 (m, 1H), 3.87-3.82 (m, 1H), 2.87-2.84 (dd, J=6.9 Hz, 5.0Hz, 6H). MS (ESI) m/z: Calculated for C₂₃H₁₉F₄N₅O₃: 489.14; found: 490.2(M+H)⁺.

Example 97N-(2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide

This compound was synthesized from2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinic acid as described inexample 8 step 6 (28 mg, yield 20%) as a yellow viscous liquid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.20 (d, J=2.3 Hz, 1H), 9.01-8.98 (m, 1H),8.80-8.77 (m, 1H), 8.51-8.48 (m, 1H), 8.21-8.19 (m, 1H), 8.01-7.96 (m,4H), 7.24-7.19 (m, 2H), 3.59-3.57 (d, J=6.2 Hz, 2H), 1.42 (s, 6H). MS(ESI) m/z: Calculated for C₂₄H₁₉F₄N₅O₂S: 517.12; found: 516.4 (M−H)⁻.

Example 98 Methyl 5-cyano-2-methoxybenzoate

A solution of acid methyl 5-cyano-2-hydroxybenzoate (2 g, 11.2 mmol) indry acetone (50 mL) was cooled to 0° C. and K₂CO₃ (2.34 g, 16.9 mmol)followed by MeI (1.1 mL, 16.9 mmol) were added dropwise. The reactionmixture was allowed to stir at 65° C. for 10 h and then diluted withEtOAc. The organic layer was washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toyield methyl 5-cyano-2-methoxybenzoate (600 mg, crude), which wascarried through without further purification. ¹H NMR (300 MHz, CDCl₃) δ8.11 (d, J=2.2 Hz, 1H), 7.78-7.74 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.08-7.05(d, J=8.8 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z: Calculatedfor C₁₀H₉NO₃: 191.06; found: 191.8 (M+H)⁺.

5-Cyano-2-methoxybenzoic acid

This compound was synthesized from 5-cyano-2-methoxybenzoic acid asdescribed in example 43 step 2 (300 mg, yield 72%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 13.13 (br s, 1H), 8.02-8.01 (d, J=2.1 Hz, 1H),7.99-7.96 (dd, J=8.8 Hz, 2.1 Hz, 1H), 7.32-7.30 (d, J=8.8 Hz, 1H), 3.90(s, 3H). MS (ESI) m/z: Calculated for C₉H₇NO₃: 177.04; found: 175.6(M−H)⁻.

5-(N′-Hydroxycarbamimidoyl)-2-methoxybenzoic acid

This compound was synthesized from 5-cyano-2-methoxybenzoic acid asdescribed in example 1 step 4 (300 mg) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₉H₁₀N₂O₄:210.06; found: 210.8 (M+H)⁺.

2-Methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

This compound was synthesized from5-(N′-hydroxycarbamimidoyl)-2-methoxybenzoic acid as described inexample 1 step 5 (40 mg, yield 35%). ¹H NMR (300 MHz, DMSO-d₆) δ 13.05(br s, 1H), 8.30-8.29 (d, J=2.2 Hz, 1H), 8.20-8.16 (dd, J=8.8 Hz, 2.2Hz, 1H), 7.38-7.35 (d, J=8.8 Hz, 1H), 3.92 (s, 3H). MS (ESI) m/z:Calculated for C₁₁H₇F₃N₂O₄: 288.04; found: 286.7 (M−H)⁻.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and2-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (40 mg, yield 36%). ¹H NMR (400 MHz, MeOD)δ 8.64-8.63 (d, J=2.3 Hz, 1H), 8.45-8.42 (t, J=5.6 Hz, 1H), 8.24-8.21(dd, J=8.8 Hz, 2.4 Hz, 1H), 8.11-8.07 (m, 2H), 7.83 (s, 1H), 7.34-7.32(d, J=8.8 Hz, 1H), 7.27-7.23 (t, J=8.8 Hz, 2H), 3.91 (s, 3H), 3.72-3.71(m, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C₂₄H₂₀F₄N₄O₄:504.14; found: 505.2 (M+H)⁺.

Example 99 2-(2-(4-Fluorophenyl)oxazol-5-yl)-2-methylpropanenitrile

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-5-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (170 mg, yield 60%). ¹H NMR (300 MHz,CDCl₃) δ 8.06-8.02 (m, 2H), 7.20-7.14 (t, J=8.7 Hz, 2H), 7.06 (s, 1H),1.81 (s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₁FN₂O: 230.09; found:230.9 (M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-5-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropanenitrile as described inexample 1 step 3 (100 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₃H₁₅FN₂O: 234.12;found: 235.2 (M+H)⁺.

N-(2-(2-(4-Fluorophenyl)oxazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (30 mg, yield 15%). ¹H NMR (400 MHz, MeOD) δ 8.48-8.47(m, 1H), 8.28-8.25 (m, 1H), 8.00-7.97 (m, 3H), 7.68-7.64 (t, J=7.8 Hz,1H), 7.21-7.16 (t, J=8.8 Hz, 2H), 7.00 (s, 1H), 3.66 (s, 2H), 1.46 (s,6H). MS (ESI) m/z: Calculated for C₂₃H₁₈F₄N₄O₃: 474.13; found: 475.2(M+H)⁺.

Example 1004-(Dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butanenitrile

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile and2-chloro-N,N-dimethylethanamine hydrochloride as described in example 16step 1b (400 mg, yield 48%). ¹H NMR (400 MHz, MeOD) δ 8.10-8.07 (m, 2H),7.99 (m, 1H), 7.29-7.25 (t, J=8.9 Hz, 2H), 4.24-4.20 (t, J=7.3 Hz, 1H),2.59-2.46 (m, 2H), 2.29 (s, 6H), 2.23-2.17 (m, 2H). MS (ESI) m/z:Calculated for C₁₅H₁₆FN₃O: 273.13; found: 274.2 (M+H)⁺.

3-(2-(4-Fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine

Cobalt (II) chloride (380 mg, 2.9 mmol) was added to a solution of4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butanenitrile (400mg, 1.46 mmol) in dry methanol (10 mL) at 0° C., followed by sodiumborohydride (550 mg, 14.6 mmol) portionwise. The resulting mixture wasstirred at room temperature for 1 h, then quenched carefully with icewater, and filtered through a Celite bed. The filtrate was concentratedunder reduced pressure to afford crude3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine (180mg, crude), which was carried through without further purification. MS(ESI) m/z: Calculated for C₁₅H₂₀FN₃O: 277.16; found: 278.2 (M+H)⁺.

N-(4-(Dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (17 mg, yield 10%). ¹H NMR (400 MHz, MeOD) δ 8.55-8.54(t, J=1.5 Hz, 1H), 8.30-8.27 (m, 1H), 8.08-8.02 (m, 3H), 7.82 (s, 1H),7.71-7.67 (t, J=7.8 Hz, 1H), 7.26-7.21 (t, J=8.9 Hz, 2H), 3.76-3.65 (m,2H), 3.16-3.10 (m, 1H), 2.53-2.40 (m, 2H), 2.30 (m, 6H), 2.04-1.98 (m,2H). MS (ESI) m/z: Calculated for C₂₄H₂₂F₄N₆O₃: 518.17; found: 519.2(M+H)⁺.

Example 101N-(4-(Dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (16 mg, yield 10%). ¹H NMR (400 MHz, MeOD) δ9.39-9.38 (d, J=2.0 Hz, 1H), 9.16 (d, J=2.0 Hz, 1H), 8.85-8.84 (t, J=2.1Hz, 1H), 8.08-8.05 (m, 2H), 7.84 (s, 1H), 7.26-7.22 (t, J=8.9 Hz, 2H),3.79-3.66 (m, 2H), 3.18-3.11 (m, 1H), 2.63-2.46 (m, 2H), 2.37 (m, 6H),2.06-2.00 (m, 2H). MS (ESI) m/z: Calculated for C₂₄H₂₂F₄N₆O₃: 518.17;found: 519.2 (M+H)⁺.

Example 102N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (120 mg, yield 45%). ¹H NMR (400 MHz, DMSO-d₆) δ9.35 (d, J=1.8 Hz, 1H), 9.27 (d, J=1.8 Hz, 1H), 9.13-9.10 (t, J=5.6 Hz,1H), 8.84-8.83 (t, J=1.8 Hz, 1H), 8.11 (s, 1H), 8.03-8.00 (dd, J=8.5 Hz,5.5 Hz, 2H), 7.39-7.35 (t, J=8.9 Hz, 2H), 5.74-5.73 (d, J=5.2 Hz, 1H),4.85-4.81 (m, 1H), 3.77-3.71 (m, 1H), 3.56-3.49 (m, 1H). MS (ESI) m/z:Calculated for C₂₀H₁₃F₄N₅O₄: 463.09; found: 464.0 (M+H)⁺.

Example 103 4-(Chloromethyl)-2-(4-chlorophenyl)oxazole

This compound was synthesized from 4-chlorobenzamide and1,3-dichloroacetone as described in example 74 step 1 (3.4 g, yield46%). ¹H NMR (300 MHz, CDCl₃) δ 8.01-7.98 (d, J=8.8 Hz, 2H), 7.72 (s,1H), 7.47-7.44 (d, J=8.8 Hz, 2H), 4.59 (d, J=0.9 Hz, 2H).

2-(2-(4-Chlorophenyl)oxazol-4-yl)acetonitrile

This compound was synthesized from4-(chloromethyl)-2-(4-chlorophenyl)oxazole as described in example 71step 2 (1.7 g, yield 53%). ¹H NMR (300 MHz, CDCl₃) δ 7.98-7.95 (d, J=8.8Hz, 2H), 7.75-7.74 (d, J=1.3 Hz, 1H), 7.47-7.44 (d, J=8.8 Hz, 2H), 3.73(d, J=1.3 Hz, 2H). MS (ESI) m/z: Calculated for C₁₁H₇ClN₂O: 218.02;found: 219.0 (M+H)⁺.

4-(2-(4-Chlorophenyl)oxazol-4-yl)-1-methylpiperidine-4-carbonitrile

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)acetonitrile as described in example 16step 1b (140 mg, yield 20%). ¹H NMR (400 MHz, CDCl₃) δ 8.00-7.97 (m,2H), 7.74 (s, 1H), 7.47-7.45 (m, 2H), 3.67-3.63 (m, 2H), 3.25-3.18 (m,2H), 2.99-2.95 (m, 2H), 2.89 (s, 3H), 2.49-2.46 (m, 2H). MS (ESI) m/z:Calculated for C₁₆H₁₆ClN₃O: 301.10; found: 302.1 (M+H)⁺.

(4-(2-(4-Chlorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methanamine

This compound was synthesized from4-(2-(4-chlorophenyl)oxazol-4-yl)-1-methylpiperidine-4-carbonitrile asdescribed in example 1 step 3 (100 mg, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₆H₂₀ClN₃O:305.13; found: 306.2 (M+H)⁺.

N-((4-(2-(4-Chlorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamidehydrochloride

This compound was synthesized from(4-(2-(4-chlorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 96 step 3 (12 mg, yield 5%). ¹H NMR (400 MHz,CDCl₃) [free amine] δ 8.56 (s, 1H), 8.28-8.26 (d, J=7.7 Hz, 1H),8.13-8.11 (d, J=7.6 Hz, 1H), 8.02-8.00 (d, J=8.5 Hz, 2H), 7.79-7.75 (m,1H), 7.66-7.62 (d, J=7.2 Hz, 1H), 7.57 (s, 1H), 7.42-7.40 (d, J=8.2 Hz,2H), 3.77-3.76 (d, J=4.7 Hz, 2H), 2.79-2.77 (m, 2H), 2.59 (m, 2H), 2.42(m, 3H), 2.22-2.21 (m, 2H), 2.08-2.04 (m, 2H). MS (ESI) m/z: Calculatedfor C₂₆H₂₃ClF₃N₅O₃: 545.14; found: 546.2 (M+H)⁺.

Example 104 2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methylpropanenitrile

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (300 mg, yield 53%). ¹H NMR (400 MHz,CDCl₃) δ 8.00-7.98 (d, J=8.7 Hz, 2H), 7.68 (s, 1H), 7.46-7.44 (d, J=8.7Hz, 2H), 1.76 (s, 6H). MS (ESI) m/z: Calculated for C₁₃H₁₁ClN₂O: 246.06;found: 247.0 (M+H)⁺.

2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropanenitrile as described inexample 1 step 3 (155 mg, yield 59%) and it was used without furtherpurification. MS (ESI) m/z: Calculated for C₁₃H₁₅ClN₂O: 250.09; found:251.1 (M+H)⁺.

2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-aminehydrochloride

2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-aminewas synthesized from3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde and2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine as described inexample 7 step 3. The free amine was then treated with HCl in dioxane (2M) at 0° C. and stirred at room temperature for 30 min. The reactionmixture was concentrated under reduced pressure. The crude was purifiedby washing with dry hexane to get2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-aminehydrochloride (20 mg, yield 6%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (br s,2H), 8.26 (s, 1H), 8.11-8.08 (m, 2H), 7.85-7.80 (m, 3H), 7.69-7.65 (t,J=7.6 Hz, 1H), 7.55-7.52 (d, J=8.5 Hz, 2H), 4.28 (br s, 2H), 3.12 (m,2H), 1.33 (s, 6H). MS (ESI) m/z: Calculated for C₂₃H₂₀ClF₃N₄O₂: 476.12;found: 477.2 (M+H)⁺.

Example 105 2-(2-(4-Fluorophenyl)oxazol-5-yl)ethanamine

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-5-yl)acetonitrile as described in example 42step 1 (70 mg) and it was carried through without further purification.MS (ESI) m/z: Calculated for C₁₁H₁₁FN₂O: 206.09; found: 206.8 (M+H)⁺.

N-(2-(2-(4-Fluorophenyl)oxazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-5-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (28 mg, yield 20%). ¹H NMR (400 MHz, MeOD) δ 8.56-8.55(m, 1H), 8.30-8.28 (dq, J=7.8 Hz, 0.9 Hz, 1H), 8.06-8.04 (m, 1H),8.00-7.96 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.71-7.69 (t, J=7.8 Hz, 1H),7.21-7.17 (t, J=8.8 Hz, 2H), 7.03 (s, 1H), 3.78-3.75 (t, J=6.7 Hz, 2H),3.15-3.12 (m, 2H). MS (ESI) m/z: Calculated for C₂₁H₁₄F₄N₄O₃: 446.10;found: 447.0 (M+H)⁺.

Example 106 4-([1,1′-Biphenyl]-3-yl)-1-methylpiperidine-4-carbonitrile

This compound was synthesized from 2-([1,1′-biphenyl]-3-yl)acetonitrileas described in example 16 step 1b (500 mg, yield 35%). ¹H NMR (400 MHz,MeOD) δ 7.75 (m, 1H), 7.64-7.60 (m, 3H), 7.53-7.51 (m, 2H), 7.48-7.44(m, 2H), 7.39-7.35 (m, 1H), 3.08-3.05 (m, 2H), 2.57-2.50 (m, 2H), 2.42(s, 3H), 2.23-2.20 (m, 4H). MS (ESI) m/z: Calculated for C₁₉H₂₀H₂:276.16; found: 277.0 (M+H)⁺.

(4-([1,1-Biphenyl]-3-yl)-1-methylpiperidin-4-yl)methanamine

This compound was synthesized from4-([1,1′-biphenyl]-3-yl)-1-methylpiperidine-4-carbonitrile as describedin example 1 step 3 (250 mg, yield 50%). ¹H NMR (400 MHz, MeOD) δ7.63-7.58 (m, 3H), 7.52-7.42 (m, 4H), 7.39-7.32 (m, 2H), 2.77 (s, 2H),2.69-2.66 (m, 2H), 2.37-2.27 (m, 4H), 2.22 (s, 3H), 1.91-1.86 (m, 2H).MS (ESI) m/z: Calculated for C₁₉H₂₄N₂: 280.19; found: 281.0 (M+H)⁺.

N-((4-([1,1′-Biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (60 mg, yield 31%) as an off white solid. ¹H NMR (400MHz, MeOD) δ 8.39 (m, 1H), 8.23-8.21 (m, 1H), 7.90-7.88 (m, 1H),7.64-7.54 (m, 4H), 7.49-7.47 (m, 3H), 7.39-7.36 (m, 2H), 7.31-7.28 (m,1H), 3.60 (m, 2H), 2.79-2.76 (m, 2H), 2.42-2.30 (m, 4H), 2.23 (m, 3H),2.11-2.06 (m, 2H). MS (ESI) m/z: Calculated for C₂₉H₂₇F₃N₄O₂: 520.21;found: 521.2 (M+H)⁺.

Example 107 4-(Chloromethyl)-2-(4-methoxyphenyl)oxazole

This compound was synthesized from 4-methoxybenzamide and1,3-dichloroacetone as described in example 74 step 1 (2.3 g, yield 78%)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.96 (d, J=8.3 Hz,2H), 7.65 (s, 1H), 6.97-6.95 (d, J=8.3 Hz, 2H), 4.56 (s, 2H), 3.86 (s,3H). MS (ESI) m/z: Calculated for C₁₁H₁₀ClNO₂: 223.04; found: 223.8(M+H)⁺.

2-(2-(4-Methoxyphenyl)oxazol-4-yl)acetonitrile

This compound was synthesized from4-(chloromethyl)-2-(4-methoxyphenyl)oxazole as described in example 71step 2 (0.65 g, yield 57%) as an off white solid. ¹H NMR (300 MHz,CDCl₃) δ 7.97-7.94 (d, J=8.6 Hz, 2H), 7.69 (s, 1H), 6.99-6.97 (d, J=8.6Hz, 2H), 3.87 (s, 3H), 3.71 (s, 2H). MS (ESI) m/z: Calculated forC₁₂H₁₀N₂O₂: 214.07; found: 214.8 (M+H)⁺.

2-(2-(4-Methoxyphenyl)oxazol-4-yl)ethanamine

This compound was synthesized from2-(2-(4-methoxyphenyl)oxazol-4-yl)acetonitrile as described in example42 step 1 (130 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₂H₁₄N₂O₂: 218.11; found:218.8 (M+H)⁺.

N-(2-(2-(4-Methoxyphenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-methoxyphenyl)oxazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (35 mg, yield 19%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 9.47 (m, 1H), 9.34 (m, 1H), 8.90-8.89 (t, J=2.0 Hz, 1H),8.08-8.06 (m, 1H), 8.03-8.00 (d, J=8.8 Hz, 2H), 7.55 (s, 1H), 6.99-6.97(d, J=8.8 Hz, 2H), 3.88 (s, 3H), 3.87-3.84 (m, 2H), 2.96-2.93 (t, J=5.9Hz, 2H). MS (ESI) m/z: Calculated for C₂₁H₁₆F₃N₅O₄: 459.12; found: 460.1(M+H)⁺.

Example 108 2-Chloro-5-cyanobenzoic acid

A solution of NaNO₂ (2.21 g, 32 mmol) in water (10 mL) was added to asolution of 5-amino-2-chlorobenzoic acid (5.0 g, 29.14 mmol) in water(40 mL) at 0° C., followed addition of by conc. HCl (10 mL) at −5° C.The reaction mixture was stirred at −5° C. for an additional 1 h andthen the diazonium solution was added dropwise into a solution ofpotassium cuprotetracyanide [prepared by dropwise addition of a solutionof KCN (10 g, 15.38 mmol) in water (18 mL) to a solution of CuSO₄ (7 g,43.8 mmol) in water (12 mL) at 70° C.] at 50° C. for 1 h. The reactionmixture was acidified with 1.5 N HCl solution and the product wasextracted with EtOAc. The combined extracts were washed with water andbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica 60-120 mesh, eluant 1-2% MeOH in CHCl₃) to get2-chloro-5-cyanobenzoic acid (1.8 g, yield 34%). ¹H NMR (400 MHz,DMSO-d₆) δ 13.92 (br s, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.02-7.99 (d, J=8.4Hz, 2.1 Hz, 1H), 7.80-7.78 (d, J=8.2 Hz, 1H). MS (ESI) m/z: Calculatedfor C₈H₄ClNO₂: 180.99; found: 179.6 (M−H)⁻.

2-Chloro-5-cyano-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and2-chloro-5-cyanobenzoic acid as described in example 8 step 6 (300 mg,yield 44%). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J=2.0 Hz, 1H), 7.98-7.95(m, 2H), 7.66-7.63 (m, 1H), 7.56-7.54 (d, J=8.3 Hz, 1H), 7.48 (s, 1H),7.39 (m, 1H), 7.17-7.13 (t, J=8.8 Hz, 2H), 3.68-3.66 (d, J=5.8 Hz, 2H),1.41 (s, 6H). MS (ESI) m/z: Calculated for C₂₁H₁₇ClFN₃O₂: 397.10; found:396.4 (M−H)⁻.

4-Chloro-3-((2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)carbamoyl)benzohydrazonicacid

This compound was synthesized from2-chloro-5-cyano-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)benzamideas described in example 1 step 4 (230 mg, crude) and it was carriedthrough without further purification. ¹H NMR (300 MHz, MeOD) δ 8.06-8.02(m, 2H), 7.74-7.73 (m, 2H), 7.67-7.63 (m, 1H), 7.46-7.43 (d, J=8.3 Hz,1H), 7.24-7.18 (t, J=8.8 Hz, 2H), 3.61 (s, 2H), 1.40 (s, 6H). MS (ESI)m/z: Calculated for C₂₁H₂₀ClFN₄O₃: 430.12; found: 429.4 (M−H)⁻.

2-Chloro-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from4-chloro-3-((2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)carbamoyl)benzohydrazonicacid as described in example 1 step 5 (100 mg, yield 37%). ¹H NMR (400MHz, MeOD) δ 8.15-8.12 (m, 2H), 8.07-8.04 (m, 2H), 7.76 (s, 1H),7.68-7.66 (m, 1H), 7.23-7.18 (m, 2H), 3.67 (s, 2H), 1.43 (s, 6H). MS(ESI) m/z: Calculated for C₂₃H₁₇ClF₄N₄O₃: 508.09; found: 509.1 (M+H)⁺.

Example 109N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (18 mg, yield 12%). ¹H NMR (400 MHz, MeOD) δ 8.55 (s,1H), 8.29 (d, J=7.8 Hz, 1H), 8.09-8.05 (m, 3H), 7.78 (s, 1H), 7.71-7.68(t, J=7.8 Hz, 1H), 7.24-7.19 (m, 2H), 3.66 (s, 2H), 1.41 (s, 6H). MS(ESI) m/z: Calculated for C₂₃H₁₈F₄N₄O₃: 474.13; found: 475.1 (M+H)⁺.

Example 110 1-(2-(4-Fluorophenyl)oxazol-4-yl)ethanone

A solution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (400 mg, 2.09mmol) in dry chloroform (5 mL) was cooled to 0° C. and a freshlyprepared solution of diazomethane in ether (20 mL) was added. Thereaction mixture was stirred for 1 h and quenched with 10% aqueousNaHCO₃ solution. The crude product was extracted with CH₂Cl₂ and thecombined extracts were dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel 60-120 mesh, eluent 5-8% EtOAc inpetroleum ether) to afford 1-(2-(4-fluorophenyl)oxazol-4-yl)ethanone(250 mg, yield 58%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s,1H), 8.12-8.09 (m, 2H), 7.21-7.17 (t, J=8.7 Hz, 2H), 2.60 (s, 3H). MS(ESI) m/z: Calculated for C₁₁H₈FNO₂: 205.05; found: 205.9 (M+H)⁺.

3-(2-(4-Fluorophenyl)oxazol-4-yl)-3-hydroxypropanenitrile

A solution of 1-(2-(4-fluorophenyl)oxazol-4-yl)ethanone (250 mg, 1.22mmol) in DMF-H₂O (7 mL; 2:5 v/v) was cooled to 0° C. and KH₂PO₄ (327 mg,2.4 mmol) was added, followed by KCN (116 mg, 1.8 mmol). The reactionmixture was stirred at 80° C. 10 h and then diluted with water. Theorganic product was extracted with EtOAc and the combined extracts werewashed with H₂O and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel 60-120 mesh, eluent 8-12% EtOAc inpetroleum ether) to afford3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropanenitrile (60 mg, yield21%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=0.7Hz, 1H), 8.03-7.98 (dd, J=8.9 Hz, 5.4 Hz, 2H), 7.40-7.34 (t J=8.9 Hz,2H), 6.13-6.12 (d, J=5.3 Hz, 1H), 4.93-4.87 (m, 1H), 2.98-2.93 (dd,J=8.9 Hz, 5.8 Hz, 2H). MS (ESI) m/z: Calculated for C₁₂H₉FN₂O₂: 232.06;found: 233.0 (M+H)⁺.

3-Amino-1-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-01

This compound was synthesized from3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropanenitrile as describedin example 94 step 6 (110 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₂H₁₃FN₂O₂: 236.10;found: 237.0 (M+H)⁺.

N-(3-(2-(4-Fluorophenyl)oxazol-4-yl)-3-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from3-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-ol and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (35 mg, yield 19%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.80-8.77 (t, J=5.3 Hz, 1H), 8.51 (s, 1H), 8.20-8.18 (d,J=7.6 Hz, 1H), 8.13-8.11 (d, J=7.9 Hz, 1H), 8.00 (s, 1H), 7.99-7.96 (dd,J=8.8 Hz, 5.5 Hz, 2H), 7.72-7.68 (t, J=7.8 Hz, 1H), 7.37-7.32 (t, J=8.8Hz, 2H), 5.44-5.43 (d, J=5.2 Hz, 1H), 4.69-4.65 (m, 1H), 3.47-3.42 (m,2H), 2.17-2.08 (m, 1H), 1.99-1.90 (m, 1H). MS (ESI) m/z: Calculated forC₂₂H₁₆F₄N₄O₄: 476.11; found: 477.1 (M+H)⁺.

Example 111 2-(4-Bromophenyl)-4-(chloromethyl)oxazole

This compound was synthesized from 4-bromobenzamide and1,3-dichloroacetone as described in example 74 step 1 (1.5 g, yield 14%)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.92-7.89 (d, J=8.8 Hz, 2H),7.71 (s, 1H), 7.61-7.59 (d, J=8.8 Hz, 2H), 4.57 (s, 2H). MS (ESI) m/z:Calculated for C₁₀H₇BrClNO: 272.94; found: 273.8 (M+H)⁺.

2-(2-(4-Bromophenyl)oxazol-4-yl)acetonitrile

This compound was synthesized from2-(4-bromophenyl)-4-(chloromethyl)oxazole as described in example 71step 2 (1.4 g, yield 76%) as a off-white solid. ¹H NMR (300 MHz, CDCl₃)δ 7.90-7.88 (d, J=8.8 Hz, 2H), 7.75-7.74 (t, J=1.3 Hz, 1H), 7.63-7.60(d, J=8.8 Hz, 2H), 3.73 (d, J=1.3 Hz, 2H). MS (ESI) m/z: Calculated forC₁₁H₇BrN₂O: 261.97; found: 262.9 (M+H)⁺.

2-(2-(4-Bromophenyl)oxazol-4-yl)ethanamine

This compound was synthesized from2-(2-(4-bromophenyl)oxazol-4-yl)acetonitrile as described in example 42step 1 (0.4 g, yield 56%) as a yellow liquid. ¹H NMR (300 MHz, DMSO-d₆)δ 8.02 (m, 1H), 7.89-7.86 (d, J=8.6 Hz, 2H), 7.73-7.71 (d, J=8.6 Hz,2H), 2.96-2.91 (m, 2H), 2.73-2.68 (m, 2H). MS (ESI) m/z: Calculated forC₁₁H₁₁BrN₂O: 266.01; found: 267.1 (M+H)⁺.

N-(2-(2-(4-Bromophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide

Triethylamine (0.31 mL, 2.24 mmol) was added to a solution of2-(2-(4-bromophenyl)oxazol-4-yl)ethanamine (0.4 g, 1.49 mmol) in drymethanol (20 mL), followed by ethyl trifluoro acetate (0.27 mL, 2.25mmol) dropwise at 0° C. The reaction mixture was slowly warmed to roomtemperature and further stirred for 2 h. The reaction mixture was thenconcentrated under reduced pressure. The reaction mixture was dilutedwith EtOAc and washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel 60-120 mesh, eluent 1%MeOH in CHCl₃) to affordN-(2-(2-(4-bromophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (0.26g, yield 48%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.98-7.95(d, J=8.6 Hz, 2H), 7.68-7.65 (d, J=8.6 Hz, 2H), 7.61 (m, 1H), 3.78-3.72(m, 2H), 2.96-2.92 (t, J=6.1 Hz, 2H). MS (ESI) m/z: Calculated forC₁₃H₁₀BrF₃N₂O₂: 361.99; found: 362.5 (M+H)⁺.

N-(2-(2-(4-Cyanophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide

N-(2-(2-(4-Bromophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (200mg, 0.55 mmol) was dissolved in dry DMF (10 mL) and the solution waspurged with argon for 10 min. Zn(CN)₂ (97 mg, 0.83 mmol) and PdCl₂(dppf)(302 mg, 0.04 mmol) were added to the reaction mixture and heated to150° C. for 48 h. The reaction mixture was filtered through Celite andthe filtrate was concentrated under reduced pressure. The residue wasdiluted with water and the product was extracted with EtOAc. Thecombined extracts were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to getN-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (150mg), which was used for the next step without further purification. MS(ESI) m/z: Calculated for C₁₄H₁₀F₃N₃O₂: 309.07; found: 307.9 (M−H)⁻.

4-(4-(2-Aminoethyl)oxazol-2-yl)benzonitrile

K₂CO₃ (0.20 g, 1.45 mmol) was added portionwise to a solution ofN-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (0.15g, 0.49 mmol) in dry methanol:water (10 mL, 7:3 v/v). The reactionmixture was stirred at room temperature for 3 h and then diluted withwater. The crude product was extracted with chloroform. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to get 4-(4-(2-aminoethyl)oxazol-2-yl)benzonitrile (80 mg),which was used for the next step without further purification. MS (ESI)m/z: Calculated for C₁₂H₁₁N₃O: 213.09; found: 214.0 (M+H)⁺.

N-(2-(2-(4-Cyanophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from4-(4-(2-aminoethyl)oxazol-2-yl)benzonitrile and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (30 mg, yield 23%) as an off white solid. ¹H NMR(400 MHz, CDCl₃) δ 9.69 (m, 1H), 9.47 (m, 1H), 9.18 (m, 1H), 8.18-8.16(d, J=8.3 Hz, 2H), 7.78-7.76 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 3.92-3.91(m, 2H), 3.05-3.02 (t, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated forC₂₁H₁₃F₃N₆O₃: 454.10; found: 453.2 (M−H)⁻.

Example 112 4-(Chloromethyl)-2-(2-fluorophenyl)oxazole

A mixture of 2-fluorobenzamide (500 mg, 3.59 mmol) and1,3-dichloroacetone (1.82 g, 14.36 mmol) was heated to 130° C. for 2 hin a sealed tube. The reaction mixture was diluted with EtOAc and washedwith water and brine. Solvent was removed under reduced pressure and thecrude product was purified by column chromatography (silica gel 60-120mesh, eluent 2-3% EtOAc in petroleum ether) to afford4-(chloromethyl)-2-(2-fluorophenyl)oxazole (500 mg, yield 66%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 8.08-8.02 (td, J=7.6 Hz, 1.6 Hz,1H), 7.78 (s, 1H), 7.50-7.43 (m, 1H), 7.28-7.18 (m, 2H), 4.61 (d, J=0.7Hz, 2H). MS (ESI) m/z: Calculated for C₁₀H₇ClFNO: 211.02; found: 211.9(M+H)⁺.

2-(2-(2-Fluorophenyl)oxazol-4-yl)acetonitrile

This compound was synthesized from4-(chloromethyl)-2-(2-fluorophenyl)oxazole as described in example 71step 2 (0.2 g, yield 29%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.05-8.00 (td, J=7.6 Hz, 1.8 Hz, 1H), 7.82-7.81 (t, J=1.3 Hz, 1H),7.50-7.45 (m, 1H), 7.30-7.20 (m, 2H), 3.77 (d, J=1.1 Hz, 2H). MS (ESI)m/z: Calculated for C₁₁H₇FN₂O: 202.05; found: 202.9 (M+H)⁺.

2-(2-(2-Fluorophenyl)oxazol-4-yl)ethanamine

This compound was synthesized from2-(2-(2-fluorophenyl)oxazol-4-yl)acetonitrile as described in example 42step 1 (100 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₁H₁₁FN₂O: 206.09; found:207.0 (M+H)⁺.

N-(2-(2-(2-Fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(2-fluorophenyl)oxazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (10 mg, yield 6%) as a white solid. ¹H NMR (400 MHz,MeOD) δ 9.39 (d, J=2.0 Hz, 1H), 9.20 (d, J=2.0 Hz, 1H), 8.90-8.89 (t,J=2.0 Hz, 1H), 8.03-7.99 (td, J=7.7 Hz, 1.8 Hz, 1H), 7.89 (s, 1H),7.56-7.51 (m, 1H), 7.33-7.25 (m, 2H), 3.80-3.76 (t, J=6.9 Hz, 2H),3.00-2.97 (t, J=6.9 Hz, 2H). MS (ESI) m/z: Calculated for C₂₀H₁₃F₄N₅O₃:447.10; found: 448.1 (M+H)⁺.

Example 113 1-(5-Bromothiophen-2-yl)-2,2-difluoroethanone

A solution of 2-bromothiophene (0.5 g, 3.00 mmol) in dry THF (5 mL) wascooled to −78° C. and freshly prepared lithium diisopropylamide(prepared from diisopropyl amine (0.5 mL, 3.60 mmol) and nBuLi (2.3 mL,3.60 mmol, 1.6M in THF) was added dropwise. The reaction mixture wasstirred at −78° C. for 1 h. Ethyl difluoro acetate (409 mg, 3.30 mmol)was added dropwise at −78° C. and the reaction mixture was stirred for 1h, then slowly warmed up to room temperature and quenched with saturatedNH₄CI solution. The organic product was extracted with EtOAc and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure to get 1-(5-bromothiophen-2-yl)-2,2-difluoroethanone(500 mg, yield 69%). ¹H NMR (400 MHz, CDCl₃) δ 7.77-7.75 (m, 1H),7.21-7.20 (d, J=4.1 Hz, 1H), 6.27-6.00 (m, 1H).

3-(5-(2,2-Difluoroacetyl)thiophen-2-yl)benzoic acid

This compound was synthesized from1-(5-bromothiophen-2-yl)-2,2-difluoroethanone as described in example 88step 3 (300 mg, yield 51%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ13.24 (br s, 1H), 8.28 (s, 1H), 8.15-8.14 (d, J=4.2 Hz, 1H), 8.09-8.06(m, 1H), 8.01-7.99 (m, 1H), 7.88-7.87 (d, J=4.2 Hz, 1H), 7.65-7.60 (t,J=7.8 Hz, 1H), 7.20-6.85 (m, 1H). MS (ESI) m/z: Calculated forC₁₃H₈F₂O₃S: 282.02; found: 280.8 (M−H)⁻.

3-(5-(2,2-Difluoroacetyl)thiophen-2-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(2,2-difluoroacetyl)thiophen-2-yl)benzoic acid as described inexample 8 step 6 (60 mg, yield 34%). ¹H NMR (400 MHz, DMSO-d₆) δ8.51-8.48 (t, J=6.2 Hz, 1H), 8.19-8.15 (m, 2H), 8.02-7.97 (m, 3H),7.90-7.88 (m, 1H), 7.84-7.83 (d, J=4.3 Hz, 1H), 7.61-7.57 (t, J=7.8 Hz,1H), 7.35-7.31 (t, J=8.8 Hz, 2H), 7.16-6.90 (m, 1H), 3.52-3.50 (d, J=6.4Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C₂₆H₂₁F₃N₂O₃S:498.12; found: 499.1 (M+H)⁺.

Example 114 1-(2-Bromothiazol-5-yl)-2,2,2-trifluoroethanol

This compound was synthesized from 2-bromothiazole-5-carbaldehyde asdescribed in example 88 step 1 (0.6 g, yield 44%). ¹H NMR (300 MHz,CDCl₃) δ 7.63 (s, 1H), 5.37-5.29 (m, 1H), 3.54 (d, J=5.0 Hz, 1H).

1-(2-Bromothiazol-5-yl)-2,2,2-trifluoroethanone

This compound was synthesized from1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethanol as described in example47 step 2 (0.35 g, yield 59%). ¹H NMR (300 MHz, CDCl₃) δ 8.32 (m, 1H).MS (ESI) m/z: Calculated for C₅HBrF₃NOS: 260.89; found: 261.0 (M+H)⁺.

3-(5-(2,2,2-Trifluoroacetyl)thiazol-2-yl)benzoic acid

This compound was synthesized from1-(2-bromothiazol-5-yl)-2,2,2-trifluoroethanone as described in example88 step 3 (120 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₂H₆F₃NO₃S: 301.00; found:299.9 (M−H)⁻.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiazol-2-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(2,2,2-trifluoroacetyl)thiazol-2-yl)benzoic acid as described inexample 8 step 6 (7 mg, yield 3%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.56-8.53(t, J=5.5 Hz, 1H), 8.35 (m, 1H), 8.28 (m, 2H), 8.10-8.08 (m, 1H),8.02-8.00 (m, 2H), 7.94 (m, 1H), 7.61-7.57 (t, J=7.8 Hz, 1H), 7.35-7.31(t, J=8.7 Hz, 2H), 3.51-3.50 (d, J=5.8 Hz, 2H), 1.29 (s, 6H). MS (ESI)m/z: Calculated for C₂₅H₁₉F₄N₃O₃S: 517.11; found: 516.1 (M−H)⁻.

Example 1154-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-phenyl-1H-imidazole

^(t)BuPh₂SiCl (5.5 g, 19.9 mmol) was added dropwise to a suspension of2-phenyl-1H-imidazole-4-methanol (2.9 g, 16.65 mmol) and imidazole (1.7g, 24.97 mmol) in dry CH₂Cl₂ (60 mL) at 0° C. The reaction mixture wasallowed to warm up to room temperature and stirred for 8 h. The reactionmixture was diluted with CH₂Cl₂ and the organic layer was washed with10% NaHCO₃ solution, water and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to yield4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-phenyl-1H-imidazole (5.7 g,yield 83%), which was carried through without further purification. ¹HNMR (300 MHz, CDCl₃) δ 7.77-7.69 (m, 6H), 7.46-7.37 (m, 9H), 6.95 (m,1H), 4.81 (s, 2H), 1.09 (s, 9H). MS (ESI) m/z: Calculated forC₂₆H₂₈N₂OSi: 412.20; found: 413.3 (M+H)⁺.

4-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-methyl-2-phenyl-1H-imidazole

This compound was synthesized from4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-phenyl-1H-imidazole asdescribed in example 1 step 2 (1.25 g, yield 21%) as a yellow viscousliquid. ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.75 (m, 3H), 7.69-7.67 (m, 4H),7.61-7.60 (m, 2H), 7.46-7.41 (m, 6H), 6.95 (s, 1H), 5.14 (d, J=1.3 Hz,2H), 3.88 (s, 3H), 1.13 (s, 9H). MS (ESI) m/z: Calculated forC₂₇H₃₀N₂OSi: 426.21; found: 427.3 (M+H)⁺.

(1-Methyl-2-phenyl-1H-imidazol-4-yl)methanol

A solution of4-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-2-phenyl-1H-imidazole(1.25 g, 2.93 mmol) in dry THF (25 mL) was cooled to 0° C. andtetrabutylammonium fluoride (5.9 mL, 5.86 mmol, 1M in THF) was addeddropwise. The reaction mixture was allowed to warm up to roomtemperature and further stirred for 3 h. The reaction mixture wasquenched with brine and extracted with EtOAc. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by column chromatography (silica 60-120 mesh,eluant 2-4% MeOH in CH₂Cl₂) to get(1-methyl-2-phenyl-1H-imidazol-4-yl)methanol (0.26 mg, yield 47%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.68-7.66 (m, 2H), 7.50-7.41(m, 3H), 7.11 (s, 1H), 4.92 (br s, 1H), 4.37 (s, 2H), 3.71 (s, 3H). MS(ESI) m/z: Calculated for C₁₁H₁₂N₂O: 188.09; found: 188.9 (M+H)⁺.

4-(Chloromethyl)-1-methyl-2-phenyl-1H-imidazole

This compound was synthesized from(1-methyl-2-phenyl-1H-imidazol-4-yl)methanol as described in example 93step 3 (0.28 g, crude) as hydrochloride salt as a brown solid. ¹H NMR(300 MHz, DMSO-d₆) δ 7.90 (s, 1H), 7.82-7.80 (m, 2H), 7.70-7.66 (m, 3H),4.93 (s, 2H), 3.84 (s, 3H).

2-(1-Methyl-2-phenyl-1H-imidazol-4-yl)acetonitrile

This compound was synthesized from4-(chloromethyl)-1-methyl-2-phenyl-1H-imidazole as described in example77 step 1 (120 mg, yield 44%) as a brown liquid. ¹H NMR (300 MHz, CDCl₃)δ 7.61-7.58 (m, 2H), 7.49-7.43 (m, 3H), 7.02 (s, 1H), 3.75 (d, J=0.9 Hz,2H), 3.73 (s, 3H). MS (ESI) m/z: Calculated for C₁₂H₁₁N₃: 197.10; found:197.9 (M+H)⁺.

2-(1-Methyl-2-phenyl-1H-imidazol-4-yl)propanenitrile

This compound was synthesized from2-(1-methyl-2-phenyl-1H-imidazol-4-yl)acetonitrile as described inexample 1 step 2 (60 mg, yield 47%) as light yellow oil. ¹H NMR (300MHz, CDCl₃) δ 7.62-7.59 (m, 2H), 7.47-7.45 (m, 3H), 7.01 (s, 1H),4.01-3.94 (q, J=7.1 Hz, 1H), 3.72 (s, 3H), 1.71-1.69 (d, J=7.2 Hz, 3H).MS (ESI) m/z: Calculated for C₁₃H₁₃N₃: 211.11; found: 212.0 (M+H)⁺.

2-(1-Methyl-2-phenyl-1H-imidazol-4-yl)propan-1-amine

This compound was synthesized from2-(1-methyl-2-phenyl-1H-imidazol-4-yl)propanenitrile as described inexample 1 step 3 (60 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₃H₁₇N₃: 215.14;found: 216.0 (M+H)⁺.

N-(2-(1-Methyl-2-phenyl-1H-imidazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(1-methyl-2-phenyl-1H-imidazol-4-yl)propan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (10 mg, yield 16%). ¹H NMR (400 MHz, CDCl₃) δ 9.40(d, J=2.1 Hz, 1H), 9.31 (d, J=2.1 Hz, 1H), 9.16-9.15 (m, 1H), 8.87-8.86(t, J=2.1 Hz, 1H), 7.62-7.59 (m, 2H), 7.42-7.40 (m, 3H), 6.81 (s, 1H),4.02-3.96 (ddd, J=12.9 Hz, 6.2 Hz, 4.3 Hz, 1H), 3.75 (s, 3H), 3.42-3.35(ddd, J=12.9 Hz, 9.4 Hz, 3.2 Hz, 1H), 3.15-3.10 (m, 1H), 1.40-1.38 (d,J=6.7 Hz, 3H). MS (ESI) m/z: Calculated for C₂₂H₁₉F₃N₆O₂: 456.15; found:457.3 (M+H)⁺.

Example 116 1-(5-Bromofuran-2-yl)-2,2,2-trifluoroethanol

This compound was synthesized from 5-bromofuran-2-carbaldehyde asdescribed in example 88 step 1 (2.6 g, yield 62%). ¹H NMR (300 MHz,CDCl₃) δ 6.52-6.51 (d, J=3.5 Hz, 1H), 6.36-6.35 (d, J=3.5 Hz, 1H),5.07-4.98 (m, 1H), 2.91-2.89 (d, J=7.2 Hz, 1H).

1-(5-Bromofuran-2-yl)-2,2,2-trifluoroethanone

This compound was synthesized from1-(5-bromofuran-2-yl)-2,2,2-trifluoroethanol as described in example 47step 2 (1.2 g, yield 47%). ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.44 (m, 1H),6.66-6.65 (d, J=3.7 Hz, 1H).

3-(5-(2,2,2-Trifluoroacetyl)furan-2-yl)benzoic acid

This compound was synthesized from1-(5-bromofuran-2-yl)-2,2,2-trifluoroethanone as described in example 88step 3 (500 mg, crude). ¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (br s, 1H),8.41 (m, 1H), 8.19-8.16 (m, 1H), 8.05-8.03 (m, 1H), 7.98-7.97 (m, 1H),7.70-7.67 (m, 1H), 7.58-7.57 (m, 1H).

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)furan-2-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(2,2,2-trifluoroacetyl)furan-2-yl)benzoic acid as described inexample 8 step 6 (20 mg, yield 6%). ¹H NMR (400 MHz, DMSO-d₆) δ8.52-8.49 (t, J=6.2 Hz, 1H), 8.30-8.29 (t, J=1.6 Hz, 1H), 8.09-8.06 (dt,J=8.1 Hz, 1.2 Hz, 1H), 8.01-7.98 (m, 4H), 7.94-7.92 (dt, J=8.1 Hz, 1.2Hz, 1H), 7.66-7.62 (t, J=7.8 Hz, 1H), 7.51-7.50 (d, J=4.0 Hz, 1H),7.35-7.31 (t, J=9.0 Hz, 2H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s, 6H).MS (ESI) m/z: Calculated for C₂₆H₂₀F₄N₂O₄: 500.14; found: 499.4 (M−H)⁻.

Example 117 4-(Dimethoxymethyl)-2-(4-fluorophenyl)oxazole

Methoxytrimethylsilane (545 mg, 5.23 mmol) and trimethylsilyltrifluoromethanesulfonate (30 mg, 0.13 mmol) were added to a solution of2-(4-fluorophenyl)oxazole-4-carbaldehyde (500 mg, 2.62 mmol) in dryCH₂Cl₂ (2 mL) at −78° C. The reaction mixture was allowed to warm up toroom temperature and stirred for 24 h, quenched with saturated aqueousNaHCO₃ solution, and the crude product was extracted with EtOAc. Theorganic layer was washed with 10% NaHCO₃ solution, water and brine anddried over anhydrous sodium sulfate. Solvent was removed under reducedpressure to get 4-(dimethoxymethyl)-2-(4-fluorophenyl)oxazole (400 mg,crude), which was carried through without further purification. ¹H NMR(400 MHz, CDCl₃) δ 8.08-8.05 (m, 2H), 7.71 (d, J=1.2 Hz, 1H), 7.16-7.12(m, 2H), 5.50 (d, J=0.9 Hz, 1H), 3.41 (s, 6H). MS (ESI) m/z: Calculatedfor C₁₂H₁₂FNO₃: 237.08; found: 259.9 (M+Na)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methoxyacetonitrile

Trimethylsilyl cyanide (4.13 g, 41.76 mmol) was added to a solution of4-(dimethoxymethyl)-2-(4-fluorophenyl)oxazole (400 mg, 1.69 mmol) atroom temperature, followed by boron trifluoride diethyl etherate (37 mg,0.26 mmol). The reaction mixture was stirred for 20 min, quenched withsaturated aqueous NaHCO₃ solution, and extracted with EtOAc. Thecombined extracts were washed with H₂O and brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica gel 60-120 mesh,eluent 8-10% EtOAc in petroleum ether) to afford2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyacetonitrile (100 mg, yield16%) as a light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.08-8.06 (m,2H), 7.90 (d, J=0.9 Hz, 1H), 7.19-7.15 (m, 2H), 5.29 (d, J=0.9 Hz, 1H),3.62 (s, 3H). MS (ESI) m/z: Calculated for C₁₂H₉FN₂O₂: 232.21; found:232.9 (M+H)⁺.

2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methoxyethanamine

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyacetonitrile as described inexample 94 step 6 (100 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₂H₁₃FN₂O₂: 236.10;found: 236.9 (M+H)⁺.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methoxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (44 mg, yield 22%) as an off-white solid. ¹H NMR (400MHz, CDCl₃) δ 8.56-8.55 (t, J=1.6 Hz, 1H), 8.29-8.26 (dt, J=7.9 Hz, 1.3Hz, 1H), 8.11-8.06 (m, 3H), 7.73 (s, 1H), 7.67-7.63 (t, J=7.7 Hz, 1H),7.22-7.19 (m, 1H), 7.17-7.13 (t, J=8.7 Hz, 2H), 4.54-4.51 (dd, J=5.9 Hz,5.1 Hz, 1H), 4.12-4.06 (ddd, J=13.9 Hz, 6.5 Hz, 4.9 Hz, 1H), 3.87-3.81(ddd, J=13.9 Hz, 6.1 Hz, 4.8 Hz, 1H), 3.45 (s, 3H). MS (ESI) m/z:Calculated for C₂₂H₁₆F₄N₄O₄: 476.11; found: 475.6 (M)⁻.

Example 118 2-(4-(4-Fluorophenyl)thiazol-2-yl)propanenitrile

To a stirred solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile(500 mg, 2.29 mmol) in THF (10 mL) at −78° C. was added LiHMDS (1M inTHF; 2.06 mL, 2.06 mmol) and the reaction mixture was stirred at −78° C.for 10 min. Iodomethane (0.12 mL, 2.06 mmol) in THF (2 mL) was thenadded dropwise and the reaction mixture was stirred at −78° C. for 30min. The reaction mixture was diluted with EtOAc, washed with saturatedaqueous NH₄CI solution, water, brine, and dried over anhydrous sodiumsulfate. The organic layer was concentrated under reduced pressure togive the crude product; which was purified on a Teledyne ISCO automatedcolumn chromatography system (0-30% EtOAc/Hexanes) to give2-(4-(4-fluorophenyl)thiazol-2-yl)propanenitrile (180 mg, yield 34%). MS(ESI) m/z: Calculated for C₁₂H₉FN₂S: 232.05; found: 233.1 (M+H)

2-(4-(4-Fluorophenyl)thiazol-2-yl)propan-1-amine

To a stirred solution of2-(4-(4-fluorophenyl)thiazol-2-yl)propanenitrile (140 mg, 0.6 mmol) inTHF (3 mL) at room temperature was added borane (1M in THF; 3.01 mL,3.01 mmol) and the reaction mixture was stirred at room temperature for1 h and then heated at 40° C. for 1 h. The reaction mixture was thencooled to 0° C. and quenched with MeOH (˜5 eq, ˜0.2 mL), and allowed towarm to room temperature where 2N HCl solution was added until the pH˜2. The reaction mixture was refluxed at 65° C. for 15 min and thencooled to room temperature and concentrated under reduced pressure. Thesolid obtained was triturated with ether twice and dichloromethaneanother two times. The remaining solid was dissolved in water (˜50 mL)and basified to pH ˜11 with NaOH pellets. The aqueous mixture was thenextracted with ether and dried over sodium sulfate and concentratedunder reduced pressure to give2-(4-(4-fluorophenyl)thiazol-2-yl)propan-1-amine (75 mg, yield 52%),which was carried through without further purification; MS (ESI) m/z:Calculated for C₁₂H₁₃FN₂S: 236.08; found: 237.1 (M+H)⁺.

N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

2-(4-(4-Fluorophenyl)thiazol-2-yl)propan-1-amine (50 mg, 0.21 mmol),3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (54.62 mg, 0.21mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(EDC) (81.12 mg, 0.42 mmol), and 1-hydroxybenzotriazole (HOBt) (45.74mg, 0.39 mmol) were dissolved in dichloromethane (3 mL) at roomtemperature. Diisopropylethylamine (DIEA) (0.147 mL, 0.85 mmol) was thenintroduced at room temperature and the reaction mixture was stirred atroom temperature overnight. The reaction mixture was diluted withdichloromethane (100 mL) and washed with water (1×20 mL) and brine (1×20mL). The organic layer was then dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the crude product, which waspurified on a Teledyne ISCO automated column chromatography system(0-30% EtOAc/Hexanes) to giveN-(2-(4-(4-fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide(36 mg, 36% yield). ¹H NMR (CDCl3) 8.50 (1 h, s), 8.23 (1H, d, J=8 Hz),8.03 (1H, 1H, d, J=8 Hz), 7.85-7.81 (3H, m), 7.58 (1H, t), 7.35 (1H, s),7.03 (2H, m), 4.05 (1H, m), 3.65 (1H, m), 1.54 (3H, d, J=8 Hz). MS (ESI)m/z: Calculated for C₂₂H₁₆F₄N₄O₂S: 476.09; found: 477.1 (M+H)⁺.

Example 119N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide

This compound was synthesized from(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described inexample 118 step 3 (0.022 g, yield 15%). ¹H NMR (400 MHz, DMSO)8.650-8.681 (t, 1H), δ 8.132 (s, 2H), δ 8.071 (s, 1H), δ 7.973-7.991 (d,1H), δ 7.897-7.915 (d, 1H), 7.826-7.846 (d, 1H), 7.786-7.797 (d, 1H),7.532-7.571 (t, 1H), 7.320-7.357 (t, 2H), 7.254-7.272 (d, 1H),3.814-3.843 (d 2H), 3.553-3.568 (d, 2H), 3.282-3.409 (d, 2H), 2.22-2.26(d, 2H), 1.936-2.006 (m, 2H); MS (ESI+) m/z 555.1 (M−H).

Example 120N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (45 mg, yield 27%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.91(t, J=5.4 Hz, 1H), 8.51 (s, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.12 (d, J=8.2Hz, 1H), 8.00-7.97 (m, 3H), 7.74-7.70 (t, J=7.8 Hz, 1H), 7.37-7.32 (t,J=8.8 Hz, 2H), 3.61-3.56 (m, 2H), 2.84-2.80 (t, J=7.0 Hz, 2H). MS (ESI)m/z: Calculated for C₂₁H₁₄F₄N₄O₃: 446.10; found: 447.2 (M+H)⁺.

Example 121N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and5-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (19 mg, yield 13%). ¹H NMR (400 MHz, MeOD) δ 9.38(d, J=1.5 Hz, 1H), 9.17 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.8 Hz, 1H),8.09-8.05 (m, 2H), 7.78 (s, 1H), 7.25-7.20 (m, 2H), 3.68 (s, 2H), 1.42(s, 6H). MS (ESI) m/z: Calculated for C₂₂H₁₇F₄N₅O₃: 475.13; found: 476.2(M+H)⁺.

Example 122 2-(3-Bromophenyl)-2-methylpropanenitrile

This compound was synthesized from 2-(3-bromophenyl)acetonitrile asdescribed in example 1 step 2 using iodomethane, (1.2 g, used crude) andit was carried through without further purification. MS (ESI) m/z:Calculated for C₁₀H₁₀BrN: 223.00; found: 224.0 (M+H)⁺.

2-(3-Bromophenyl)-2-methylpropan-1-amine

This compound was synthesized from2-(3-bromophenyl)-2-methylpropanenitrile as described in example 1 step3 (1.3 g, used crude), and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₀H₁₄BrN: 227.03; found:228.0 (M+H)⁺.

N-(2-(3-Bromophenyl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(3-bromophenyl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (90 mg, yield 83%). MS (ESI) m/z: Calculated forC₂₀H₁₇BrF₃N₃O₂: 467.05; found: 468.0 (M+H)⁺.

N-(2-([1,1′-Biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

A solution ofN-(2-(3-bromophenyl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide(30 mg, 0.064 mmol) and phenyl boronic acid (39 mgs, 0.32 mmol) in THF(1.2 mL) was degassed with nitrogen.Dichloro[1,1′bis(di-tert-butylphosphino)]ferrocene palladium (II) (5mgs, 0.006 mmol) and 1 M potassium carbonate (1.2 mL) were added. Thereaction was heated overnight at 60° C. The reaction was extracted withethyl acetate and dried over sodium sulfate. The crude was purified byprep TLC using 30% EA/hexanes to yieldN-(2-([1,1′-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide(6 mgs, yield 18%). ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H) 8.18 (d,J=7.2 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.64-7.30 (m, 10H) 5.88 (s, 1H),3.73 (d, J=7.2 Hz, 2H), 1.48 (s, 6H). MS (ESI) m/z: Calculated forC₂₆H₂₂F₃N₃O₂: 465.17; found: 466.2 (M+H)⁺.

Example 123N-(2-(4′-Fluoro-[1,1′-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized fromN-(2-(3-bromophenyl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamideand 4-fluoroboronic acid as described in example 122 step 4 (8 mg, 25%yield). 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H) 8.18 (d, J=7.2 Hz, 1H),7.82 (d, J=7.2 Hz, 1H), 7.60-7.38 (m, 8H) 7.11 (m, 1H), 5.71 (s, 1H),3.73 (d, J=7.2 Hz, 2H), 1.47 (s, 6H). MS (ESI) m/z: Calculated forC₂₆H₂₁F₄N₃O₂: 483.16; found: 484.2 (M+H)⁺.

Example 124 2-(4-(3,5-Difluorophenyl)thiazol-2-yl)acetonitrile

This compound was synthesized from2-bromo-1-(3,5-difluorophenyl)ethanone as described in example 1 step 1(3 g, yield 94%). MS (ESI) m/z: Calculated for C₁₁H₆F₂N₂S: 236.02;found: 237.1 (M+H)⁺.

4-(4-(3,5-Difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile

This compound was synthesized from2-(4-(3,5-difluorophenyl)thiazol-2-yl)acetonitrile using 2-bromoethylether as described in example 1 step 2 (1.0 g, yield 59%). MS (ESI) m/z:Calculated for C₁₅H₁₂F₂N₂OS: 306.06; found: 307.1 (M+H)⁺.

(4-(4-(3,5-Difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine

This compound was synthesized from4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrileas described in example 1 step 3 (1 g, crude), and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₁₅H₁₆F₂N₂OS: 310.10; found: 311.1 (M+H)⁺.

N-((4-(4-(3,5-Difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from(4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamineand 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid asdescribed in example 8 step 6 (20 mg, 10% yield). ¹H NMR (300 MHz,CDCl₃) δ 8.45 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H),7.64-7.54 (m, 2H), 7.35 (d, J=5.5 Hz, 1H), 6.73 (m, 2H), 3.95 (m, 2H),3.85 (d, J=5.5 Hz, 2H), 3.70 (m, 2H), 2.28 (m, 2H), 2.05 (m, 2H). MS(ESI) m/z: Calculated for C₂₅H₁₃F₅N₄O₃S: 550.11; found: 551.1 (M+H)⁺.

Example 1252-(4-(3,5-Difluorophenyl)thiazol-2-yl)-2-methylpropanenitrile

This compound was synthesized from2-(4-(3,5-difluorophenyl)thiazol-2-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (1.0 g, yield 60%). MS (ESI) m/z:Calculated for C₁₃H₁₀F₂N₂S: 264.05; found: 265.1 (M+H)⁺.

2-(4-(3,5-Difluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(4-(3,5-difluorophenyl)thiazol-2-yl)-2-methylpropanenitrile asdescribed in example 1 step 3 (1 g, crude) and it was carried throughwithout further purification. MS (ESI) m/z: Calculated for C₁₃H₁₄F₂N₂S:268.08; found: 269.1 (M+H)⁺.

N-(2-(4-(3,5-Difluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(4-(3,5-difluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (85 mg, yield 24%). ¹H NMR (300 MHz, CDCl₃) δ 8.54 (s,1H), 8.25 (d, J=7.6 Hz, 1H), 8.04 (m, 1H) 7.62 (t, J=9.2 Hz, 1H), 7.47(s, 1H), 7.35 (d, J=7.6 Hz, 2H), 6.72 (m, 1H), 3.79 (d, J=2.8 Hz, 2H),1.55 (s, 6H). MS (ESI) m/z: Calculated for C₂₃H₁₇F₅N₄O₂S: 508.10; found:509.1 (M+H)⁺.

Example 126 2-(2-Phenyloxazol-4-yl)ethanamine

This compound was synthesized from 2-(2-phenyloxazol-4-yl)acetonitrileas described in example 64 step 4 (400 mg, crude) and it was carriedthrough without further purification. MS (ESI) m/z: Calculated forC₁₁H₁₂N₂O: 188.09; found: 189.1 (M+H)⁺.

N-(2-(2-Phenyloxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from 2-(2-phenyloxazol-4-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (40 mgs, yield 25%). ¹H NMR (CDCl₃) 8.59 (s, 1H), 8.26(d, J=7.8 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.05 (m, 2H), 7.62-7.56 (m,3H), 7.43 (m, 2H), 3.84 (m, 2H), 2.93 (m, 2H). MS (ESI) m/z: Calculatedfor C₂₁H₁₅F₃N₄O₃: 428.11; found: 429.1 (M+H)⁺.

Example 127N-(2-(2-Phenyloxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from 2-(2-phenyloxazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (42 mgs, yield 32%). ¹H NMR (CDCl₃) 9.46 (d, J=2.1Hz, 1H), 9.32 (d, J=2.1 Hz, 1H), 8.87 (t, J=2.7 Hz, 1H), 8.06-7.96 (m,3H), 7.57-7.44 (m, 3H), 3.85 (m, 2H), 2.93 (t, J=6.3 Hz, 2H). MS (ESI)m/z: Calculated for C₂₀H₁₄F₃N₅O₃: 429.10; found: 430.1 (M+H)⁺.

Example 128 2-(2-(4-Chlorophenyl)oxazol-4-yl)ethanamine

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)acetonitrile as described in example 64step 4 (466 mg, crude) and it was carried through without furtherpurification. MS (ESI) m/z: Calculated for C₁₁H₁₁ClN₂₀: 222.06; found:223.1 (M+H)⁺.

N-(2-(2-(4-Chlorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)ethanamine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (4 mgs, 2% yield). ¹H NMR (CDCl₃) 8.55 (s, 1H), 8.25(d, J=7.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.8 Hz, 2H),7.68-7.54 (m, 2H), 7.41 (d, J=8.4 Hz, 2H), 3.86 (m, 2H), 3.94 (m, 2H).MS (ESI) m/z: Calculated for C₂₁H₁₄ClF₃N₄O₃: 462.07; found: 463.1(M+H)⁺.

Example 129N-(2-(2-(4-Chlorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)ethanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (14 mgs, 10% yield). ¹H NMR (CDCl₃) 9.45 (s, 1H),9.29 (s, 1H), 8.84 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.57(s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 3.85 (d, J=5.1 Hz, 2H),2.93 (t, J=5.4 Hz, 2H). MS (ESI) m/z: Calculated for C₂₀H₁₃ClF₃N₅O₃:463.07; found: 464.1 (M+H)⁺.

Example 130N-(2-Methyl-2-(2-phenyloxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-methyl-2-(2-phenyloxazol-4-yl)propan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (19 mgs, 13% yield). ¹H NMR (CDCl₃) 9.45 (t, J=9.0Hz, 1H), 9.35 (s, 1H), 8.42 (s, 1H), 8.03 (s, 2H), 7.51-7.40 (m, 4H),3.62 (bs, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C₂₂H₁₈F₃N₅O₃:457.14; found: 458.1 (M+H)⁺.

Example 131 2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methylpropanenitrile

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (100 mg, crude) and it was carried throughwithout further purification MS (ESI) m/z: Calculated for C₁₃H₁₁ClN₂O:246.06; found: 247.1 (M+H)⁺.

2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropanenitrile as described inexample 1 step 3 (100 mg, crude) and it was carried through withoutfurther purification. MS (ESI) m/z: Calculated for C₁₃H₁₅ClN₂O: 250.09;found: 251.1 (M+H)⁺.

N-(2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (8 mg, yield 14%). ¹H NMR (CDCl₃) 8.59 (t, J=1.7 Hz,1H), 8.25 (d, J=7.9 Hz, 1H), 8.12 (d, J=6.7 Hz, 1H), 7.99 (d, J=6.6 Hz,2H), 7.64 (t, J=7.7 Hz, 2H) 7.49 (s, 1H), 7.38 (d, J=4.9 Hz, 1H), 2.03(s, 2H), 1.40 (s, 6H). MS (ESI) m/z: Calculated for C₂₃H₁₈ClF₃N₄O₃:490.10; found: 491.1 (M+H)⁺.

Example 132 Methyl3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propanoate

This compound was synthesized from methyl 3-aminopropanoate and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (120 mgs, yield 75%). MS (ESI) m/z: Calculated forC₁₄H₁₂F₃N₃O₄: 343.08; found: 344.1 (M+H)⁺.

3-(3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propanoic acid

A sodium hydroxide solution (0.2 mL, 5 M) was added to a solution ofmethyl3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propanoate inTHF/MeOH/water (4:1:1, 15 mL). The reaction was stirred for 30 min andacidified with 2 M HCl. The reaction was extracted with ethyl acetateseveral times, dried over sodium sulfate, and used crude. MS (ESI) m/z:Calculated for C₁₃H₁₀F₃N₃O₄: 329.06; found: 330.1 (M+H)⁺.

N-(2-(3-Phenyl-1,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

HOBt (47 mg, 0.35 mmol), EDCI (67 mg, 0.35 mmol), anddiisopropylethylamine (0.7 mL, 1.0 mmol) were added to a solution of3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propanoic acid(115 mg, 0.35 mmol) and N′-hydroxybenzimidamide (47 mg, 0.35 mmol) indichloromethane (3.5 mL) with a few drops of DMF. The reaction wasstirred 1 h and then toluene was added and the reaction was heated to90° C. for 1 h. The reaction was diluted with ethyl acetate and theorganic layer was washed with saturated sodium bicarbonate and driedover sodium sulfate. The product was purified on reverse phase usingwater/acetonitrile to giveN-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide(10 mg, yield 7%). ¹H NMR (CDCl₃) 8.60 (s, 1H), 8.22 (m, 1H), 8.10 (m,3H,) 7.60 (m, 1H), 7.55-7.45 (m, 3H), 4.05 (m, 2H), 3.26 (m, 2H). MS(ESI) m/z: Calculated for C₂₀H₁₄F₃N₅O₃: 429.10; found: 430.1 (M+H)⁺.

Example 133 Ethyl 1-benzyl-5-phenyl-1H-pyrazole-3-carboxylate

Benzyl bromide (696 mg, 4.01 mmol) was added to ethyl5-phenyl-1H-pyrazole-3-carboxylate (880 mg, 4.1 mmol) and potassiumcarbonate (562 mg, 4.01) in DMF (8 mL). The reaction was stirred forseveral h and then diluted with water. The mixture was washed severaltimes with ethyl acetate and the combine extracts were dried over sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified on ISCO using 0-100% ethyl acetate/hexane gradient to giveethyl 1-benzyl-5-phenyl-1H-pyrazole-3-carboxylate (1.3 g, quantitative).MS (ESI) m/z: Calculated for C₁₉H₁₈N₂O₂: 306.14; found: 307.1 (M+H)⁺.

(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)methanol

At 0° C., LAH (1.8 mL, 3.7 mmol, 2M in THF) was added to ethyl1-benzyl-5-phenyl-1H-pyrazole-3-carboxylate (560 mg, 1.8 mmol) in THF(18 mL). The reaction was stirred for 10 min and then warmed to roomtemperature for 1 h. Minimal water was slowly added to the reactionfollowed by 1 mL of 5 M sodium hydroxide. The reaction was stirred for30 min, sodium sulfate was added, and the solids were removed byfiltration. The filtrate was concentrated under reduced pressure toyield crude (1-benzyl-5-phenyl-1H-pyrazol-3-yl)methanol, which wascarried through without further purification. MS (ESI) m/z: Calculatedfor C₁₇H₁₆N₂O: 264.13; found: 265.1 (M+H)⁺.

1-Benzyl-3-(bromomethyl)-5-phenyl-1H-pyrazole

Carbon tetrabromide (2.5 g, 7.6 mmol) and then triphenylphosphine (2.0g, 7.6 mmol) was added to (1-benzyl-5-phenyl-1H-pyrazol-3-yl)methanol(1.0 g, 3.8 mmol) in dicholomethane (38 mL) at 0° C. Upon completion ofthe reaction as monitored by LCMS, the reaction was filtered throughsilica washing with methylene chloride and then purified on an ISCOusing 0-30% ethyl acetate/hexanes to give1-benzyl-3-(bromomethyl)-5-phenyl-1H-pyrazole (0.5 g, yield 43%). MS(ESI) m/z: Calculated for C₁₇H₁₅BrN₂: 326.04; found: 327.0 (M+H)⁺.

2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)acetonitrile

1-Benzyl-3-(bromomethyl)-5-phenyl-1H-pyrazole (200 mg, 0.6 mmol) andsodium cyanide (30 mg, 0.6 mmol) were stirred in DMF (6 mL). Afterseveral h, more sodium cyanide (60 mg, 1.2 mmol) was added to thereaction. A 25% ammonium hydroxide solution in water was added to thereaction and the reaction mixture was extracted with ethyl acetate. Thecombined extracts were dried over sodium sulfate and concentrated underreduced pressure to yield2-(1-benzyl-5-phenyl-1H-pyrazol-3-yl)acetonitrile (130 mg, yield 80%) MS(ESI) m/z: Calculated for C₁₈H₁₅N₃: 273.13; found: 274.1 (M+H)⁺.

2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile

This compound was synthesized from2-(1-benzyl-5-phenyl-1H-pyrazol-3-yl)acetonitrile using iodomethane asdescribed in example 1 step 2 (500 mg, yield 91%). MS (ESI) m/z:Calculated for C₂₀H₁₉N₃: 301.16; found: 302.2 (M+H)⁺.

2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-amine

2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (50 mg,0.16 mmol) was dissolved in THF (1.6 mL). Borane-tetrahydrofuran (0.8mL, 1 M solution) was added and the reaction was heated to 60° C. for 3h. Minimal water was added to quench the reaction. Ethyl acetate wasadded followed by sodium sulfate and the solids were removed byfiltration. The filtrate was concentrated under reduced pressure toyield 2-(1-benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-amine (50mg, crude), which was carried through without further purification. MS(ESI) m/z: Calculated for C₂₀H₂₃N₃: 305.19; found: 306.2 (M+H)⁺.

2-Methyl-2-(5-phenyl-1H-pyrazol-3-yl)propan-1-amine

2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-amine (50 mg, 0.2mmol) was stirred under an atmosphere of hydrogen inmethanol/concentrated sulfuric acid (5:1, 5 mL) with 5% palladium oncarbon (350 mg). After several h, more palladium on carbon was added(350 mg). The reaction was stopped after 3 days with starting materialremaining. The solution was degassed and filtered through Celite.Methanol was removed under vacuum and 1 M potassium carbonate was addeduntil the reaction was basic. The slurry was extracted multiple timeswith 30% isopropanol/chloroform. The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure to yield2-methyl-2-(5-phenyl-1H-pyrazol-3-yl)propan-1-amine, which was carriedthrough without further purification.

N-(2-Methyl-2-(3-phenyl-1H-pyrazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from2-methyl-2-(5-phenyl-1H-pyrazol-3-yl)propan-1-amine and3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described inexample 8 step 6 (10 mg, yield 11%). ¹H NMR (CDCl₃) 8.52 (s, 1H) 8.20(d, J=7.4, 1H), 8.05 (d, J=7.4, 1H), 7.64-7.52 (m, 3H), 7.46-7.32 (m,3H), 6.47 (s, 1H), 3.70 (d, J=4.5, 2H), 1.44 (s, 6H). MS (ESI) m/z:Calculated for C₂₃H₂₀F₃N₅O₂: 455.16; found: 456.2 (M+H)⁺.

Example 134N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (75 mg, yield 28%) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 9.47-9.46 (d, J=2.0 Hz, 1H), 9.33 (d, J=2.0 Hz, 1H),8.88-8.87 (t, J=2.1 Hz, 1H), 8.11-8.04 (m, 3H), 7.54 (d, J=1.0 Hz, 1H),7.18-7.14 (t, J=8.8 Hz, 2H), 4.02-3.96 (ddd, J=13.2 Hz, 6.5 Hz, 4.1 Hz,1H), 3.53-3.46 (ddd, J=13.1 Hz, 9.0 Hz, 4.3 Hz, 1H), 3.20-3.11 (m, 1H),1.42-1.40 (d, J=7.0 Hz, 3H). MS (ESI) m/z: Calculated for C₂₁H₁₅F₄N₅O₃:461.11; found: 462.1 (M+H)⁺.

Example 135N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (18 mg, yield 16%). ¹H NMR (400 MHz, CDCl₃) δ 9.46(d, J=2.0 Hz, 1H), 9.23 (d, J=2.3 Hz, 1H), 8.80 (t, J=2.1 Hz, 1H), 8.21(m, 1H), 7.81-7.78 (m, 2H), 7.43 (m, 1H), 7.38-7.35 (m, 2H), 3.85 (d,J=5.8 Hz, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated forC₂₂H₁₇ClF₃N₅O₂S: 507.07; found: 508.0 (M+H)⁺.

Example 136N-((4-([1,1′-Biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

This compound was synthesized from(4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methanamine and5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as describedin example 8 step 6 (60 mg, yield 30%) as an off white solid. ¹H NMR(400 MHz, MeOD) δ 9.32 (d, J=2.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H),8.68-8.67 (t, J=2.0 Hz, 1H), 7.65 (m, 1H), 7.57-7.55 (m, 2H), 7.50-7.47(m, 3H), 7.40-7.36 (t, J=7.4 Hz, 2H), 7.31-7.28 (m, 1H), 3.62 (m, 2H),2.79-2.76 (m, 2H), 2.44-2.31 (m, 4H), 2.24 (m, 3H), 2.11-2.05 (m, 2H).MS (ESI) m/z: Calculated for C₂₈H₂₆F₃N₅O₂: 521.20; found: 522.2 (M+H)⁺.

Example 137 5-Bromothiophene-3-carbaldehyde

Anhydrous aluminum chloride (5.9 g, 44.5 mmol) was added in smallportions over a period of 2 h to a solution of thiophene-3-carbaldehyde(2.0 g, 17.8 mmol) in CH₂Cl₂ (100 mL) maintaining the temperature at 0°C. Bromine (2.56 g, 16.0 mmol) in CH₂Cl₂ (50 mL) was then added dropwiseto the reaction mixture at 0° C. The reaction mixture was refluxed at40° C. for 1 h, quenched with water, and extracted with CH₂Cl₂. Thecombined extracts were dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure. The crude product was purified by columnchromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether)to give 5-bromothiophene-3-carbaldehyde (3.0 g, yield 88%).

1-(5-Bromothiophen-3-yl)-2,2,2-trifluoroethanol

This compound was synthesized from 5-bromothiophene-3-carbaldehyde asdescribed in example 88 step 1 (3.0 g, yield 73%) as a yellow liquid. ¹HNMR (300 MHz, CDCl₃) δ 7.36 (s, 1H), 7.15 (s, 1H), 5.05-5.03 (m, 1H),3.28 (br s, 1H).

1-(5-Bromothiophen-3-yl)-2,2,2-trifluoroethanone

This compound was synthesized from1-(5-bromothiophen-3-yl)-2,2,2-trifluoroethanol as described in example47 step 2 (1.85 g, yield 62%). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (m, 1H),7.62 (d, J=1.1 Hz, 1H).

3-(4-(2,2,2-Trifluoroacetyl)thiophen-2-yl)benzoic acid

This compound was synthesized from1-(5-bromothiophen-3-yl)-2,2,2-trifluoroethanone and3-carboxyphenylboronic acid as described in example 88 step 3 (150 mg,yield 16%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (br s,1H), 8.85 (s, 1H), 8.19 (s, 1H), 8.07-8.05 (m, 2H), 7.96-7.93 (d, J=7.9Hz, 1H), 7.62-7.57 (t, J=7.7 Hz, 1H).

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(4-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(4-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described inexample 8 step 6 (75 mg, yield 30%). ¹H NMR (400 MHz, DMSO-d₆) δ8.21-8.16 (m, 1H), 8.11-8.10 (m, 1H), 8.02-7.96 (m, 3H), 7.91-7.90 (m,1H), 7.88-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.67-7.48 (m, 2H), 7.31-7.25(m, 2H), 3.56-3.54 (m, 2H), 1.33 (d, J=2.1 Hz, 6H). MS (ESI) m/z:Calculated for C₂₆H₂₀F₄N₂O₃S: 516.11; found: 515.7 (M−H)⁻.

Example 138N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-oxoethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized fromN-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamideas described in example 47 step 2 (150 mg, yield 43%) as an off-whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.62 (t, J=1.5 Hz, 1H), 8.40 (s, 1H),8.32-8.29 (dt, J=7.8 Hz, 1.2 Hz, 1H), 8.15-8.11 (m, 3H), 7.70-7.65 (t,J=7.8 Hz, 1H), 7.25-7.19 (t, J=8.7 Hz, 3H), 5.02-5.00 (d, J=4.6 Hz, 2H).MS (ESI) m/z: Calculated for C₂₁H₁₂F₄N₄O₄: 460.08; found: 459.4 (M−H)⁻.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-oxoethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide(150 mg, 0.33 mmol) was dissolved in dry THF (10 mL) and the reactionmixture was cooled to −50° C. Methylmagnesium chloride (0.32 mL, 0.98mmol, 3M in THF) was then added and the reaction mixture was stirred at−50° C. for 3 h. The reaction mixture was quenched with aqueoussaturated NH₄Cl solution, and extracted with EtOAc. The combinedextracts were washed with water and brine, and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 25-30% EtOAc in petroleumether) followed by preparative TLC (eluent 30% EtOAc in petroleum ether)to affordN-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide(15 mg, yield 10%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (t,J=1.5 Hz, 1H), 8.28-8.25 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.05-8.01 (m, 3H),7.70 (s, 1H), 7.64-7.61 (t, J=7.8 Hz, 1H), 7.16-7.11 (t, J=8.7 Hz, 2H),7.05-7.02 (m, 1H), 3.96-3.85 (m, 2H), 3.81 (s, 1H), 1.65 (s, 3H). MS(ESI) m/z: Calculated for C₂₂H₁₆F₄N₄O₄: 476.11; found: 475.5 (M−H)⁻.

Example 139 1-(4-Bromofuran-2-yl)-2,2,2-trifluoroethanol

This compound was synthesized from 4-bromofuran-2-carbaldehyde asdescribed in example 88 step 1 (1.0 g, yield 72%) as a pale yellowliquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=0.9 Hz, 1H), 7.10-7.08(d, J=6.4 Hz, 1H), 6.75 (s, 1H), 5.29-5.22 (m, 1H).

1-(4-Bromofuran-2-yl)-2,2,2-trifluoroethanone

This compound was synthesized from1-(4-bromofuran-2-yl)-2,2,2-trifluoroethanol as described in example 47step 2 (0.8 g, yield 81%), which was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (m, 1H), 7.52-7.51(m, 1H).

3-(5-(2,2,2-Trifluoroacetyl)furan-3-yl)benzoic acid

This compound was synthesized from1-(4-bromofuran-2-yl)-2,2,2-trifluoroethanone and 3-carboxyphenylboronicacid as described in example 88 step 3 (150 mg, yield 26%) as a paleyellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.14 (br s, 1H), 8.99 (s,1H), 8.44 (s, 1H), 8.31 (m, 1H), 8.07-8.04 (m, 1H), 7.93-7.90 (m, 1H),7.60-7.55 (t, J=7.7 Hz, 1H). MS (ESI) m/z: Calculated for C₁₃H₇F₃O₄:284.03; found: 282.9 (M−H)⁻.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)furan-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(2,2,2-trifluoroacetyl)furan-3-yl)benzoic acid as described inexample 8 step 6 (30 mg, yield 14%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.91(s, 1H), 8.40-8.35 (m, 2H), 8.16 (m, 1H), 8.02-7.94 (m, 4H), 7.82-7.80(m, 1H), 7.57-7.53 (t, J=7.8 Hz, 1H), 7.36-7.31 (t, J=9.0 Hz, 2H),3.53-3.51 (d, J=6.1 Hz, 2H), 1.30 (s, 6H). MS (ESI) m/z: Calculated forC₂₆H₂₀F₄N₂O₄: 500.14; found: 499.5 (M−H)⁻.

Example 140 1-(4-Bromothiophen-2-yl)-2,2,2-trifluoroethanol

This compound was synthesized from 4-bromothiophene-2-carbaldehyde asdescribed in example 88 step 1 (2.0 g, yield 74%) as a pale yellowliquid. ¹H NMR (300 MHz, CDCl₃) δ 7.30 (d, J=1.3 Hz, 1H), 7.12 (m, 1H),5.27-5.22 (m, 1H), 3.17 (br s, 1H).

1-(4-Bromothiophen-2-yl)-2,2,2-trifluoroethanone

This compound was synthesized from1-(4-bromothiophen-2-yl)-2,2,2-trifluoroethanol as described in example47 step 2 (1.5 g, yield 75%) as dark brown liquid. ¹H NMR (300 MHz,CDCl₃) δ 7.86 (m, 1H), 7.80 (d, J=0.9 Hz, 1H).

3-(5-(2,2,2-Trifluoroacetyl)thiophen-3-yl)benzoic acid

This compound was synthesized from1-(4-bromothiophen-2-yl)-2,2,2-trifluoroethanone and3-carboxyphenylboronic acid as described in example 88 step 3 (400 mg,yield 46%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (brs, 1H), 8.85 (d, J=1.2 Hz, 1H), 8.50 (s, 1H), 8.29 (m, 1H), 8.10-8.08(d, J=7.6 Hz, 1H), 7.96-7.94 (d, J=7.6 Hz, 1H), 7.62-7.59 (t, J=7.8 Hz,1H). MS (ESI) m/z: Calculated for C₁₃H₇F₃O₃S: 300.01; found: 298.9(M−H)⁻.

N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-3-yl)benzamide

This compound was synthesized from2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and3-(5-(2,2,2-trifluoroacetyl)thiophen-3-yl)benzoic acid as described inexample 8 step 6 (30 mg, yield 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.67(d, J=1.2 Hz, 1H), 8.43 (m, 1H), 8.16-8.12 (m, 2H), 8.00-7.97 (dd, J=9.0Hz, 5.3 Hz, 2H), 7.92-7.90 (m, 2H), 7.84-7.82 (m, 1H), 7.57-7.53 (t,J=7.8 Hz, 1H), 7.30-7.25 (t, J=9.0 Hz, 2H), 3.56 (d, J=6.4 Hz, 2H), 1.34(s, 6H). MS (ESI) m/z: Calculated for C₂₆H₂₀F₄N₂O₃S: 516.11; found:515.5 (M−H)⁻.

Example 1413-Cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

This compound was synthesized from(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and3-cyanobenzoic acid as described in example 8 step 6 (6.6 g, yield 89%)as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.11-8.10 (m, 1H), 8.02-7.99(dt, J=7.9 Hz, 1.5 Hz, 1H), 7.91-7.88 (m, 2H), 7.78-7.74 (dt, J=7.7 Hz,1.3 Hz, 1H), 7.71-7.68 (m, 1H), 7.53-7.46 (m, 3H), 7.42-7.36 (m, 1H),3.97-3.90 (m, 2H), 3.85-3.83 (d, J=5.7 Hz, 2H), 3.77-3.69 (m, 2H),2.35-2.29 (m, 2H), 2.07-1.98 (m, 2H). MS (ESI) m/z: Calculated forC₂₃H₂₁N₃O₂S: 403.14; found: 402.2 (M−H)⁻.

(N′-Hydroxycarbamimidoyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

This compound was synthesized from3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamideas described in example 1 step 4 (6.8 g, crude), which was used withoutfurther purification. ¹H NMR (400 MHz, MeOD) δ 8.05-8.04 (m, 1H),7.93-7.91 (m, 2H), 7.78-7.75 (m, 3H), 7.43-7.37 (m, 3H), 7.32-7.28 (m,1H), 3.94-3.91 (m, 2H), 3.69 (m, 2H), 3.63-3.56 (m, 2H), 2.43-2.39 (d,J=13.8 Hz, 2H), 2.10-2.06 (m, 2H). MS (ESI) m/z: Calculated forC₂₃H₂₄N₄O₃S: 436.16; found: 437.2 (M+H)⁺.

Ethyl3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-1,2,4-oxadiazole-5-carboxylate

3-(N′-Hydroxycarbamimidoyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide(6.8 g, 15.57 mmol) was dissolved in anhydrous pyridine (68 mL) and thereaction mixture was cooled to 0° C. Ethyl chlorooxoacetate (5.2 mL,46.73 mmol) was added dropwise, and the reaction mixture was heated at60° C. for 1 h, quenched with 1.5N HCl solution, and diluted with EtOAc.The organic layer was washed with water and brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica gel 60-120 mesh,eluent 25-30% EtOAc in petroleum ether) to afford ethyl3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-1,2,4-oxadiazole-5-carboxylate(6.8 g, yield 87%). ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=7.9 Hz, 1H),8.11-8.09 (m, 1H), 7.78-7.76 (m, 1H), 7.61-7.59 (m, 2H), 7.44 (s, 1H),7.32-7.27 (m, 1H), 7.23-7.21 (m, 3H), 4.62-4.57 (q, J=7.0 Hz, 2H),3.97-3.94 (m, 2H), 3.81-3.76 (m, 2H), 3.56-3.50 (m, 2H), 2.41-2.37 (m,2H), 2.19-2.12 (m, 2H), 1.53-1.50 (t, J=7.2 Hz, 3H). MS (ESI) m/z:Calculated for C₂₇H₂₆N₄O₅S: 518.16; found: 517.1 (M−H)⁻.

3-(5-(Hydroxymethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

Ethyl3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-1,2,4-oxadiazole-5-carboxylate(1.0 g, 1.93 mmol) was dissolved in anhydrous THF (20 mL) and thereaction mixture was cooled to 0° C. Lithium borohydride (1.15 mL, 2.3mmol, 2M in THF) was added, and the reaction mixture was stirred for 30min, quenched with ice, and diluted with EtOAc. The organic layer waswashed with water and brine, and concentrated under reduced pressure.The crude product was purified by column chromatography (silica gel60-120 mesh, eluant: 70-80% EtOAc in petroleum ether) to afford3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide(300 mg, yield 32%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (m, 1H), 8.20-8.17(m, 1H), 7.96 (m, 1H), 7.91-7.88 (m, 2H), 7.62 (m, 1H), 7.53-7.51 (m,2H), 7.36-7.34 (m, 3H), 4.89 (s, 2H), 3.99-3.92 (m, 2H), 3.90-3.88 (d,J=5.7 Hz, 2H), 3.78-3.70 (m, 2H), 2.35-2.27 (m, 2H), 2.08-2.00 (m, 2H).MS (ESI) m/z: Calculated for C₂₅H₂₄N₄O₄S: 476.15; found: 475.7 (M−H)⁻.

3-(5-Formyl-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

This compound was synthesized from3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamideas described in example 47 step 2 (340 mg, yield 57%). ¹H NMR (300 MHz,CDCl₃) δ 9.89 (s, 1H), 8.49 (m, 1H), 8.27-8.17 (m, 1H), 8.04-8.01 (m,1H), 7.90-7.88 (m, 2H), 7.71-7.69 (m, 1H), 7.60-7.52 (m, 2H), 7.37-7.30(m, 2H), 4.00-3.92 (m, 2H), 3.91-3.89 (d, J=5.7 Hz, 2H), 3.78-3.71 (m,2H), 2.36-2.28 (m, 2H), 2.09-2.01 (m, 2H). MS (ESI) m/z: Calculated forC₂₅H₂₂N₄O₄S: 474.14; found: 473.4 (M−H)⁻.

N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoro-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized from3-(5-formyl-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamideas described in example 88 step 1 (30 mg, yield 17%). MS (ESI) m/z:Calculated for C₂₆H₂₃F₃N₄O₄S: 544.14; found: 545.2 (M+H)⁺.

N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)-1,2,4-oxadiazol-3-yl)benzamide

This compound was synthesized fromN-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoro-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl)benzamideas described in example 47 step 2 (5 mg, yield 17%). ¹H NMR (400 MHz,CDCl₃) δ 8.56 (s, 1H), 8.15-8.13 (m, 1H), 7.89-7.87 (m, 2H), 7.79-7.77(m, 1H), 7.54 (s, 1H), 7.44-7.36 (m, 4H), 4.00-3.94 (m, 2H), 3.90-3.89(d, J=5.3 Hz, 2H), 3.79-3.74 (m, 2H), 2.34-2.30 (m, 2H), 2.07-2.02 (m,2H). MS (ESI) m/z: Calculated for C₂₆H₂₁F₃N₄O₄S: 542.12; found: 541.5(M−H)⁻.

Pharmaceutical Compositions Example A

Tablets are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound of Example I  5 mgMicrocrystalline cellulose 100 mg Lactose 100 mg Sodium starchglycollate  30 mg Magnesium stearate  2 mg Total 237 mg

Example B

Capsules are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound of Example 3  15 mg Dried starch178 mg Magnesium stearate  2 mg Total 195 mg

Histone Deacetylase 9 (HDAC9) Inhibition Assay:

Novel histone deacetylase 9 (HDAC9) inhibitors were characterized in anin vitro biochemical functional assay. The assay measures the increasedfluorescent signal due to deacetylation, by HDAC9, of a fluorogenicsubstrate. The commercial available substrate is Class IIa HDAC-specificand contains an acetylated lysine residue and would releases thefluorescent signal upon trypsin cleavage after deacetylation.

Specifically, test compounds diluted to various concentrations in 100%DMSO are first dispensed into 384-well assay plates. Recombinant HDAC9isoform 4 (purchased from BPS Bioscience) in complete assay buffer (50mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂, 0.05% BSA &0.005% Tween 20) were then added to each well (5 uL/well) usingMultidrop Combi (Thermo Scientific), followed by 5 uL/well substrate(purchased from BPS Bioscience, 4.5 uM final). After 45 minutesincubation at room temperature, 10 uL 2× developer solution (assaybuffer with 40 uM Trypsin and 20 uM Trichostatin A) was added. Theplates were then incubated 1 hour at room temperature before reading influorescent intensity mode at 450 nm in an Envision (Perkin Elmer) platereader. Percent Inhibition of HDAC9 activity by compounds in each testwells was calculated by normalizing to fluorescent signal in controlwells containing DMSO only. The pIC50s value of test compounds werecalculated from non-linear curve fitting, using ActivityBase5 dataanalysis tool (IDBS), from 11 point 3× dilution series starting from 100uM final compound concentration.

For dose response experiments, normalized data were fit by ABASE/XC50using the equation y=a+(b−a)/(1+(10̂x/10̂c)̂d), where a is the minimum %activity, b is the maximum % activity, c is the pIC₅₀, d is the Hillslope.

The pIC₅₀s are averaged to determine a mean value, for a minimum of 2experiments. As determined using the above method, the compounds ofExamples 1-141 exhibited a pIC₅₀ greater than 4.8. For instance, thecompounds of Examples 21, 32, 78, 110 and 132 inhibited HDAC9 in theabove method with a mean pIC₅₀>6.

REFERENCES

-   US 20060269559, U.S. Pat. No. 7,521,044, WO2007084775-   “Deacetylase inhibition promotes the generation and function of    regulatory T cells,” R. Tao, E. F. de Zoeten, E. O″ zkaynak, C.    Chen, L. Wang, P. M. Porrett, B. Li, L. A. Turka, E. N. Olson, M. I.    Greene, A. D. Wells, W. W. Hancock, Nature Medicine, 13 (11), 2007.-   “Expression of HDAC9 by T Regulatory Cells Prevents Colitis in    Mice,” E. F. de Zoeten, L. Wang, H. Sai, W. H. Dillmann, W. W.    Hancock, Gastroenterology. 2009 Oct. 28.-   “Immunomodulatory effects of deacetylase inhibitors: therapeutic    targeting of FOXP3+ regulatory T cells,” L. Wang, E. F. de    Zoeten, M. I. Greene and W. W. Hancock, Nature Review Drug    Discovery. 8(12):969-81, 2009 and references therein.-   “HDAC7 targeting enhances FOXP3+ Treg function and induces long-term    allograft survival,” L. Wang, et al., Am. J. Transplant 9, S621    (2009).-   “Selective class II HDAC inhibitors impair myogenesis by modulating    the stability and activity of HDAC-MEF2 complexes,” A. Nebbioso, F.    Manzo, M. Miceli, M. Conte, L. Manente, A. Baldi, A. De Luca, D.    Rotili, S. Valente, A. Mai, A. Usiello, H. Gronemeyer, L. Altucci,    EMBO reports 10 (7), 776-782, 2009. and references therein.-   “Myocyte Enhancer Factor 2 and Class II Histone Deacetylases Control    a Gender-Specific Pathway of Cardioprotection Mediated by the    Estrogen Receptor,” E. van Rooij, J. Fielitz, L. B.    Sutherland, V. L. Thijssen, H. J. Crijns, M. J. Dimaio, J.    Shelton, L. J. De Windt, J. A. Hill, E. N. Olson, Circulation    Research, January 2010.

What is claimed is:
 1. A compound according to the Formula:

wherein: R¹ is halo(C₁-C₄)alkyl, wherein said halo(C₁-C₄)alkyl containsat least 2 halo atoms; A is optionally substituted (C₃-C₆)cycloalkyl,phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, or 9-10 membered heteroaryl, wherein any optionallysubstituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, orheteroaryl is optionally substituted by 1-3 groups independentlyselected from (C₁-C₄)alkyl, halogen, cyano, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A); Z is —C(═O)NR^(X)—, —NR^(X)C(═O)NR^(X),—NR^(X)C(═O)—, —SO₂—, —SO₂NR^(X)—, —NR^(X)SO₂—, —NHCH(CF₃)—,—CH(CF₃)NH—, —CH(CF₃)—, —(C₁-C₄)alkyl-, —NR^(X)—, or—(C₁-C₃)alkyl-NR^(X)—; n is 1-4 and R² and R³ are independently selectedfrom H, fluoro, and optionally substituted (C₁-C₄)alkyl,aryl(C₁-C₄)alkyl-, and (C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, wherein, when nis 1, R² is F and R³ is H, then Z is —C(═O)NR^(X)—, —NR^(X)C(═O)NR^(X),—SO₂NR^(X)—, —NHCH(CF₃)—, —CH(CF₃)NH—, —CH(CF₃)—, —(C₁-C₄)alkyl-,—NR^(X)—, or —(C₁-C₃)alkyl-NR^(X)—, or n is 1-4 and R² is selected from—NR^(A)R^(B), —(C₁-C₄)alkyl-NR^(A)R^(B), —CONR^(A)R^(B),—(C₁-C₄)alkyl-CONR^(A)R^(B), —CO₂H, —(C₁-C₄)alkyl-CO₂H, hydroxyl,hydroxy(C₁-C₄)alkyl-, (C₁-C₃)alkoxy, and (C₁-C₃)alkoxy(C₁-C₄)alkyl-, andR³ is selected from H and optionally substituted (C₁-C₄)alkyl,aryl(C₁-C₄)alkyl-, and (C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, wherein the aryl,cycloalkyl and each of the (C₁-C₄)alkyl moieties of said optionallysubstituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and(C₃-C₇)cycloalkyl(C₁-C₄)alkyl- of any R² and R³ are optionallysubstituted by 1, 2 or 3 groups independently selected from halogen,cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,—NR^(A)R^(A), —((C₁-C₄)alkyl)NR^(A)R^(A), and hydroxyl; or n is 0-4 andR² and R³ taken together with the atom to which they are connected forman optionally substituted 4, 5, 6, or 7 membered cycloalkyl orheterocycloalkyl group, wherein said heterocycloalkyl group contains 1or 2 heteroatoms independently selected from N, O and S and saidoptionally substituted cycloalkyl or heterocycloalkyl group isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, halogen, cyano, aryl(C₁-C₄)alkyl-,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, —OR^(Y), —NR^(Y)R^(Y), —C(═O)OR^(Y),—C(═O)NR^(Y)R^(Y), —NR^(Y)C(═O)R^(Y), —SO₂NR^(Y)R^(Y), —NR^(Y)SO₂R^(Y),—OC(═O)NR^(Y)R^(Y), —NR^(Y)C(═O)OR^(Y), and —NR^(Y)C(═O)NR^(Y)R^(Y); andL is 5-6 membered heteroaryl or phenyl which is substituted by R⁴ and isoptionally further substituted, wherein when L is further substituted, Lis substituted by 1 or 2 substituents independently selected fromhalogen, cyano and (C₁-C₄)alkyl; R⁴ is H, (C₁-C₄)alkyl, halo,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkoxy,((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkyl-, (C₁-C₄)haloalkoxy-,(C₁-C₄)alkylamino, optionally substituted (C₃-C₆)cycloalkyl, optionallysubstituted phenyl, optionally substituted 5-6 memberedheterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkylor heteroaryl is optionally substituted by 1, 2 or 3 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio-, halo(C₁-C₄)alkoxy,hydroxyl, —NR^(A)R^(C) and —((C₁-C₄)alkyl)NR^(A)R^(C); or L-R⁴, takentogether, form a 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein saidbenzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionallysubstituted by 1, 2 or 3 groups independently selected from(C₁-C₄)alkyl, halogen, cyano, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio-, halo(C₁-C₄)alkoxy, hydroxyl, —NR^(A)R^(C) and—((C₁-C₄)alkyl)NR^(A)R^(C); wherein each R^(A) is independently selectedfrom H and (C₁-C₄)alkyl; R^(B) is H, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,—C(═O)(C₁-C₄)alkyl, —C(═O)O(C₁-C₄)alkyl, —C(═O)NH₂,—C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)((C₁-C₄)alkyl),—SO₂(C₁-C₄)alkyl, or R^(A) and R^(B) taken together with the atom towhich they are attached form a 4-6 membered heterocyclic ring,optionally containing one additional heteroatom selected from N, O and Sand optionally substituted by (C₁-C₄)alkyl; R^(C) is H, (C₁-C₄)alkyl,phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, orR^(A) and R^(C) taken together with the atom to which they are attachedform a 4-8 membered heterocyclic ring, optionally containing oneadditional heteroatom selected from N, O and S and optionallysubstituted by (C₁-C₄)alkyl; each R^(X) is independently selected fromH, (C₁-C₆)alkyl, and optionally substituted (C₂-C₆)alkyl, where saidoptionally substituted (C₂-C₆)alkyl is optionally substituted byhydroxyl, cyano, amino, (C₁-C₄)alkoxy, (C₁-C₄)alkyl)NH—, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)N—; and each R^(Y) is independently selectedfrom H, (C₁-C₄)alkyl, phenyl, and —(C₁-C₄)alkylphenyl; or a saltthereof.
 2. The compound or salt according to claim 1, wherein R¹ isCHF₂ or CF₃.
 3. The compound or salt according to claim 2, wherein R¹ isCF₃.
 4. The compound or salt according to claim 1, wherein A is a phenylgroup optionally substituted by 1-2 groups independently selected from(C₁-C₄)alkyl, halogen, cyano, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, —NR^(A)R^(A) and —((C₁-C₄)alkyl)NR^(A)R^(A).
 5. Thecompound or salt according to claim 1, wherein A is an unsubstitutedphenyl group or a phenyl group substituted by an ethyl, fluoro, cyano ormethoxy group.
 6. The compound or salt according to claim 1, wherein Ais a cyclopropyl, cyclopentyl or cyclohexyl group, optionallysubstituted by 1-2 groups independently selected from methyl, ethyl,tert-butyl, methoxy, ethoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A), where each R^(A) is independently H ormethyl; or A is naphthyl, optionally substituted by 1-2 groupsindependently selected from (C₁-C₄)alkyl, halogen, cyano,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A); or A is isoquinolyl, indazolyl,tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl; or A isoxazolyl, pyrazolyl, or thienyl, optionally substituted by a methylgroup or A is a pyridyl or pyridyl-N-oxide group optionally substitutedby 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl,methoxy, ethoxy, trifluoromethoxy, cyano, —NR^(A)R^(A) and—((C₁-C₄)alkyl)NR^(A)R^(A), where each R^(A) is independently H ormethyl.
 7. The compound or salt according to claim 1, wherein Z is—C(═O)NH— or —CH₂NH—.
 8. The compound or salt according to claim 1,wherein n is 0 or
 1. 9. The compound or salt according to claim 8,wherein both R² and R³ are C₁₋₄alkyl.
 10. The compound or salt accordingto claim 8, wherein both R² and R³ are H or both R² and R³ are methyl orR² is hydroxyl and R³ is H or methyl.
 11. The compound or salt accordingto claim 8, wherein R² and R³ taken together with the atom to which theyare connected form an optionally substituted 4, 5 or 6 memberedcycloalkyl or heterocycloalkyl group, wherein said heterocycloalkylgroup contains 1 heteroatom selected from N and O and said optionallysubstituted cycloalkyl or heterocycloalkyl group is optionallysubstituted by a substituent selected from (C₁-C₄)alkyl,aryl(C₁-C₂)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-.
 12. The compoundor salt according to claim 8, wherein R² and R³ taken together with theatom to which they are connected form a tetrahydropyranyl,2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl,cyclopropyl, cyclohexyl, 1-ethyl-piperidinyl, tetrahydrofuranyl,piperidinyl, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl,1-cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl,1-methyl-azetidinyl, 1-benzyl-azetidinyl, or1-cyclopropylmethyl-azetidinyl group.
 13. The compound or salt accordingto claim 1, wherein L is a 5-membered heteroaryl, pyridyl or phenylwhich is substituted by R⁴ and is optionally further substituted,wherein when L is further substituted, L is substituted by 1 substituentselected from chloro, fluoro, cyano and methyl.
 14. The compound or saltaccording to claim 1, wherein L is thiazolyl, thienyl, triazolyl,pyridyl, phenyl, or oxazolyl which is substituted by a methyl group. 15.The compound or salt according to claim 13, wherein R⁴ is H, methyl,bromo, trifluoromethyl, dimethylaminoethoxy-, dimethylaminopropyl-, andoptionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl,imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl,piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionallysubstituted by 1-2 substituents independently selected from methyl,chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano.
 16. Thecompound or salt according to claim 1, wherein L-R⁴, taken together,form a 1,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl,2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, benzimidazolyl,benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinylgroup, optionally substituted with 1 or 2 groups independently selectedfrom methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl,and morpholinylpropyl-.
 17. The compound or salt according to claim 1,wherein each R^(A) and R^(B) is independently selected from H and(C₁-C₄)alkyl.
 18. The compound or salt according to claim 1, whereinsaid salt is a pharmaceutically acceptable salt.
 19. A compound whichis:N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide,N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinamide,3-(5-(2,2-difluoroacetyl)thiophen-2-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)benzamide,N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzamide,or a pharmaceutically-acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising the compound, or pharmaceutically acceptable saltthereof, according to claim 1 and one or morepharmaceutically-acceptable excipients.